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Heal the heart through gut (hormone) ghrelin: a potential player to combat heart failure

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Abstract

Ghrelin, a small peptide hormone (28 aa), secreted mainly by X/A-like cells of gastric mucosa, is also locally produced in cardiomyocytes. Being an orexigenic factor (appetite stimulant), it promotes release of growth hormone (GH) and exerts diverse physiological functions, viz. regulation of energy balance, glucose, and/or fat metabolism for body weight maintenance. Interestingly, administration of exogenous ghrelin significantly improves cardiac functions in CVD patients as well as experimental animal models of heart failure. Ghrelin ameliorates pathophysiological condition of the heart in myocardial infarction, cardiac hypertrophy, fibrosis, cachexia, and ischemia reperfusion injury. This peptide also exerts significant impact at the level of vasculature leading to lowering high blood pressure and reversal of endothelial dysfunction and atherosclerosis. However, the molecular mechanism of actions elucidating the healing effects of ghrelin on the cardiovascular system is still a matter of conjecture. Some experimental data indicate its beneficial effects via complex cellular cross talks between autonomic nervous system and cardiovascular cells, some other suggest more direct receptor–mediated molecular actions via autophagy or ionotropic regulation and interfering with apoptotic and inflammatory pathways of cardiomyocytes and vascular endothelial cells. Here, in this review, we summarise available recent data to encourage more research to find the missing links of unknown ghrelin receptor–mediated pathways as we see ghrelin as a future novel therapy in cardiovascular protection.

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References

  1. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K (1999) Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 402:656–660

    PubMed  CAS  Google Scholar 

  2. Date Y, Kojima M, Hosoda H, Sawaguchi A, Mondal MS, Suganuma T, Matsukura S, Kangawa K, Nakazato M (2000) Ghrelin, a novel growth hormone-releasing acylated peptide, is synthesized in a distinct endocrine cell type in the gastrointestinal tracts of rats and humans. Endocrinology 141:4255–4261

    PubMed  CAS  Google Scholar 

  3. Ghelardoni S, Carnicelli V, Frascarelli S, Ronca-Testoni S, Zucchi R (2006) Ghrelin tissue distribution: comparison between gene and protein expression. J Endocrinol Investig 29:115–121

    CAS  Google Scholar 

  4. Tokudome T, Otani K, Miyazato M, Kangawa K (2019) Ghrelin and the heart. Peptides 111:42–46

    PubMed  CAS  Google Scholar 

  5. Muller TD, Nogueiras R, Andermann ML, Andrews ZB, Anker SD, Argente J, Batterham RL, Benoit SC, Bowers CY, Broglio F, Casanueva FF, DAlessio D, Depoortere I, Geliebter A, Ghigo E, Cole PA, Cowley M, Cummings DE, Dagher A, Diano S et al (2015) Ghrelin. Mol Metab 4:437–460

    PubMed  PubMed Central  CAS  Google Scholar 

  6. Yang J, Brown MS, Liang G, Grishin NV, Goldstein JL (2008) Identification of the acyltransferase that octanoylates ghrelin, an appetite-stimulating peptide hormone. Cell 132:387–396

    PubMed  CAS  Google Scholar 

  7. Murtuza MI, Isokawa M (2018) Endogenous ghrelin-O-acyltransferase (GOAT) acylates local ghrelin in the hippocampus. J Neurochem 144:58–67

    PubMed  CAS  Google Scholar 

  8. Davenport AP, Bonner TI, Foord SM, Harmar AJ, Neubig RR, Pin JP, Spedding M, Kojima M, Kangawa K (2005) International Union of Pharmacology. LVI. Ghrelin receptor nomenclature, distribution, and function. Pharmacol Rev 57:541–546

    PubMed  CAS  Google Scholar 

  9. Ikenoya C, Takemi S, Kaminoda A, Aizawa S, Ojima S, Gong Z, Chacrabati R, Kondo D, Wada R, Tanaka T, Tsuda S, Sakai T, Sakata I (2018) β-Oxidation in ghrelin-producing cells is important for ghrelin acyl-modification. Sci Rep 8:9176

    PubMed  PubMed Central  Google Scholar 

  10. Rusu CC, Racasan S, Moldovan D, Potra A, Tirinescu D, Budurea C, Orasan R, Patiu IM, Bondor C, Vladutiu D, Delean D, Danu A, Kacso IM (2018) Ghrelin and acyl ghrelin levels are associated with inflammatory and nutritional markers and with cardiac and vascular dysfunction parameters in hemodialysis patients. Int Urol Nephrol 50:1897–1906

    PubMed  CAS  Google Scholar 

  11. Andrews ZB (2019) The next big LEAP2 understanding ghrelin function. J Clin Invest 129:3542–3544

    PubMed  PubMed Central  Google Scholar 

  12. Ogawa T, de Bold AJ (2014) The heart as an endocrine organ. Endocr Connect 3:31–44

    Google Scholar 

  13. Glembotski CC (2011) Functions for the cardiomyokine, MANF, in cardioprotection, hypertrophy and heart failure. J Mol Cell Cardiol 51:512–517

    PubMed  CAS  Google Scholar 

  14. Sullivan R, McGirr R, Hu S, Tan A, Wu D, Charron C, Lalonde T, Arany E, Chakrabarti S, Luyt L, Dhanvantari S (2018) Changes in the cardiac GHSR1a-ghrelin system correlate with myocardial dysfunction in diabetic cardiomyopathy in mice. J Endocr Soc 2:178–189

    PubMed  CAS  Google Scholar 

  15. Yuan MJ, Wang T, Kong B, Wang X, Huang CX, Wang D (2016) GHSR-1a is a novel pro-angiogenic and anti-remodeling target in rats after myocardial infarction. Eur J Pharmacol 788:218–225

    PubMed  CAS  Google Scholar 

  16. Celik O, Celik N, Aydin S, Aygun BK, Haberal ET, Kuloglu T, Ulas M, Aktun LH, Acet M, Celik S (2016) Ghrelin action on GnRH neurons and pituitary gonadotropes might be mediated by GnIH-GPR147 system. Horm Mol Biol Clin Investig, vol 25:121–128

    CAS  Google Scholar 

  17. Thompson NM, Gill DA, Davies R, Loveridge N, Houston PA, Robinson IC, Wells T (2004) Ghrelin and des-octanoyl ghrelin promote adipogenesis directly in vivo by a mechanism independent of the type 1a growth hormone secretagogue receptor. Endocrinology 145:234–242

    PubMed  CAS  Google Scholar 

  18. Lilleness BM, Frishman WH (2016) Ghrelin and the cardiovascular system. Cardiol Rev 24:288–297

    PubMed  Google Scholar 

  19. Seim I, Jeffery PL, Thomas PB, Walpole CM, Maugham M, Fung JN, Yap PY, OKeeffe AJ, Lai J, Whiteside EJ, Herington AC, Chopin LK (2016) Multi-species sequence comparison reveals conservation of ghrelin gene-derived splice variants encoding a truncated ghrelin peptide. Endocrine 52:609–617

    PubMed  PubMed Central  CAS  Google Scholar 

  20. Delporte C (2013) Structure and physiological actions of ghrelin. Scientifica (Cairo) 2013:518909

    Google Scholar 

  21. Zhu X, Cao Y, Voogd K, Voodg K, Steiner DF (2006) On the processing of proghrelin to ghrelin. J Biol Chem 281:38867–38870

    PubMed  CAS  Google Scholar 

  22. Gutierrez JA, Solenberg PJ, Perkins DR, Willency JA, Knierman MD, Jin Z, Witcher DR, Luo S, Onyia JE, Hale JE (2008) Ghrelin octanoylation mediated by an orphan lipid transferase. Proc Natl Acad Sci U S A 105:6320–6325

    PubMed  PubMed Central  CAS  Google Scholar 

  23. Delhanty PJ, Neggers SJ, van der Lely AJ (2013) Des-acyl ghrelin: a metabolically active peptide. Endocr Dev 25:112–121

    PubMed  CAS  Google Scholar 

  24. Hosoda H, Kojima M, Mizushima T, Shimizu S, Kangawa K (2003) Structural divergence of human ghrelin. Identification of multiple ghrelin-derived molecules produced by post-translational processing. J Biol Chem 278:64–70

    PubMed  CAS  Google Scholar 

  25. Howard AD, Feighner SD, Cully DF, Arena JP, Liberator PA, Rosenblum CI, Hamelin M, Hreniuk DL, Palyha OC, Anderson J, Paress PS, Diaz C, Chou M, Liu KK, McKee KK, Pong SS, Chaung LY, Elbrecht A, Dashkevicz M, Heavens R et al (1996) A receptor in pituitary and hypothalamus that functions in growth hormone release. Science 273:974–977

    PubMed  CAS  Google Scholar 

  26. Wierup N, Sundler F, Heller RS (2014) The islet ghrelin cell. J Mol Endocrinol 52:35–49

    Google Scholar 

  27. Camina JP (2006) Cell biology of the ghrelin receptor. J Neuroendocrinol 18:65–76

    PubMed  CAS  Google Scholar 

  28. Callaghan B, Furness JB (2014) Novel and conventional receptors for ghrelin, desacyl-ghrelin, and pharmacologically related compounds. Pharmacol Rev 66:984–1001

    PubMed  CAS  Google Scholar 

  29. Baldanzi G, Filigheddu N, Cutrupi S, Catapano F, Bonissoni S, Fubini A, Malan D, Baj G, Granata R, Broglio F, Papotti M, Surico N, Bussolino F, Isgaard J, Deghenghi R, Sinigaglia F, Prat M, Muccioli G, Ghigo E, Graziani A (2002) Ghrelin and des-acyl ghrelin inhibit cell death in cardiomyocytes and endothelial cells through ERK1/2 and PI 3-kinase/AKT. J Cell Biol 159:1029–1037

    PubMed  PubMed Central  CAS  Google Scholar 

  30. Gnanapavan S, Kola B, Bustin SA, Morris DG, McGee P, Fairclough P, Bhattacharya S, Carpenter R, Grossman AB, Korbonits M (2002) The tissue distribution of the mRNA of ghrelin and subtypes of its receptor, GHS-R, in humans. J Clin Endocrinol Metab 87:2988

    PubMed  CAS  Google Scholar 

  31. Leung PK, Chow KB, Lau PN, Chu KM, Chan CB, Cheng CH, Wise H (2007) The truncated ghrelin receptor polypeptide (GHS-R1b) acts as a dominant-negative mutant of the ghrelin receptor. Cell Signal 19:1011–1022

    PubMed  CAS  Google Scholar 

  32. Bednarek MA, Feighner SD, Pong SS, McKee KK, Hreniuk DL, Silva MV, Warren VA, Howard AD, Van Der Ploeg LH, Heck JV (2000) Structure-function studies on the new growth hormone-releasing peptide, ghrelin: minimal sequence of ghrelin necessary for activation of growth hormone secretagogue receptor 1a. J Med Chem 43:4370–4376

    PubMed  CAS  Google Scholar 

  33. Toshinai K, Yamaguchi H, Sun Y, Smith RG, Yamanaka A, Sakurai T, Date Y, Mondal MS, Shimbara T, Kawagoe T, Murakami N, Miyazato M, Kangawa K, Nakazato M (2006) Des-acyl ghrelin induces food intake by a mechanism independent of the growth hormone secretagogue receptor. Endocrinology 147:2306–2314

    PubMed  CAS  Google Scholar 

  34. Bodart V, Bouchard JF, McNicoll N, Escher E, Carriere P, Ghigo E, Sejlitz T, Sirois MG, Lamontagne D, Ong H (1999) Identification and characterization of a new growth hormone-releasing peptide receptor in the heart. Circ Res 85:796–802

    PubMed  CAS  Google Scholar 

  35. Muccioli G, Broglio F, Valetto MR, Ghe C, Catapano F, Graziani A, Papotti M, Bisi G, Deghenghi R, Ghigo E (2000) Growth hormone-releasing peptides and the cardiovascular system. Ann Endocrinol (Paris) 61:27–31

    CAS  Google Scholar 

  36. Papotti M, Ghe C, Cassoni P, Catapano F, Deghenghi R, Ghigo E, Muccioli G (2000) Growth hormone secretagogue binding sites in peripheral human tissues. J Clin Endocrinol Metab 85:3803–3807

    PubMed  CAS  Google Scholar 

  37. Cao JM, Ong H, Chen C (2006) Effects of ghrelin and synthetic GH secretagogues on the cardiovascular system. Trends Endocrinol Metab 17:13–18

    PubMed  CAS  Google Scholar 

  38. Beiras-Fernandez A, Kreth S, Weis F, Ledderose C, Pöttinger T, Dieguez C, Beiras A, Reichart B (2010) Altered myocardial expression of ghrelin and its receptor (GHSR-1a) in patients with severe heart failure. Peptides 31:2222–2228

    PubMed  CAS  Google Scholar 

  39. Lacerda-Miranda G, Soares VM, Vieira AK, Lessa JG, Rodrigues-Cunha AC, Cortez E, Garcia-Souza EP, Moura AS (2012) Ghrelin signaling in heart remodeling of adult obese mice. Peptides 35:65–73

    PubMed  CAS  Google Scholar 

  40. Kleinz MJ, Maguire JJ, Skepper JN, Davenport AP (2006) Functional and immunocytochemical evidence for a role of ghrelin and des-octanoyl ghrelin in the regulation of vascular tone in man. Cardiovasc Res 69:227–235

    PubMed  CAS  Google Scholar 

  41. Vestergaard ET, Andersen NH, Hansen TK, Rasmussen LM, Moller N, Sorensen KE, Sloth E, Jorgensen JO (2007) Cardiovascular effects of intravenous ghrelin infusion in healthy young men. Am J Physiol Heart Circ Physiol 293:H3020–H3026

    PubMed  CAS  Google Scholar 

  42. Freeman JN, do Carmo JM, Adi AH, da Silva AA (2013) Chronic central ghrelin infusion reduces blood pressure and heart rate despite increasing appetite and promoting weight gain in normotensive and hypertensive rats. Peptides 42:35–42

    PubMed  PubMed Central  CAS  Google Scholar 

  43. Nagaya N, Uematsu M, Kojima M, Ikeda Y, Yoshihara F, Shimizu W, Hosoda H, Hirota Y, Ishida H, Mori H, Kangawa K (2001) Chronic administration of ghrelin improves left ventricular dysfunction and attenuates development of cardiac cachexia in rats with heart failure. Circulation 104:1430–1435

    PubMed  CAS  Google Scholar 

  44. Soeki T, Kishimoto I, Schwenke DO, Tokudome T, Horio T, Yoshida M, Hosoda H, Kangawa K (2008) Ghrelin suppresses cardiac sympathetic activity and prevents early left ventricular remodeling in rats with myocardial infarction. Am J Physiol Heart Circ Physiol 294:H426–H432

    PubMed  CAS  Google Scholar 

  45. Chang L, Ren Y, Liu X, Li WG, Yang J, Geng B, Weintraub NL, Tang C (2004) Protective effects of ghrelin on ischemia/reperfusion injury in the isolated rat heart. J Cardiovasc Pharmacol 43:165–170

    PubMed  CAS  Google Scholar 

  46. Khatib MN, Shankar A, Kirubakaran R, Agho K, Simkhada P, Gaidhane S, Saxena DUB, Gode D, Gaidhane A, Zahiruddin SQ (2015) Effect of ghrelin on mortality and cardiovascular outcomes in experimental rat and mice models of heart failure: a systematic review and meta-analysis. PLoS One 10:e0126697

    PubMed  PubMed Central  Google Scholar 

  47. Nagaya N, Moriya J, Yasumura Y, Uematsu M, Ono F, Shimizu W, Ueno K, Kitakaze M, Miyatake K, Kangawa K (2004) Effects of ghrelin administration on left ventricular function, exercise capacity, and muscle wasting in patients with chronic heart failure. Circulation 110:3674–3679

    PubMed  CAS  Google Scholar 

  48. Lu L, Liu M, Sun R, Zheng Y, Zhang P (2015) Myocardial infarction: symptoms and treatments. Cell Biochem Biophys 72:865–867

    PubMed  CAS  Google Scholar 

  49. Eid RA, Zaki MSA, Al-Shraim M, Eleawa SM, El-Kott AF, Al-Hashem FH, Eldeen MA, Ibrahim H, Aldera H, Alkhateeb MA (2018) Subacute ghrelin administration inhibits apoptosis and improves ultrastructural abnormalities in remote myocardium post-myocardial infarction. Biomed Pharmacother 101:920–928

    PubMed  CAS  Google Scholar 

  50. Mao Y, Tokudome T, Otani K, Kishimoto I, Nakanishi M, Hosoda H, Miyazato M, Kangawa K (2012) Ghrelin prevents incidence of malignant arrhythmia after acute myocardial infarction through vagal afferent nerves. Endocrinology 153:3426–3434

    PubMed  CAS  Google Scholar 

  51. Schwenke DO, Tokudome T, Kishimoto I, Horio T, Shirai M, Cragg PA, Kangawa K (2008) Early ghrelin treatment after myocardial infarction prevents an increase in cardiac sympathetic tone and reduces mortality. Endocrinology 149:5172–5176

    PubMed  CAS  Google Scholar 

  52. Schwenke DO, Tokudome T, Kishimoto I, Horio T, Cragg PA, Shirai M, Kangawa K (2012) One dose of ghrelin prevents the acute and sustained increase in cardiac sympathetic tone after myocardial infarction. Endocrinology 153:2436–2443

    PubMed  CAS  Google Scholar 

  53. Matsumoto M, Yasuda S, Miyazaki S, Kataoka Y, Hosoda H, Nagaya N, Noguchi T, Morii I, Ogawa H, Kangawa K (2013) Decreased serum ghrelin levels in patients with acute myocardial infarction. Tohoku J Exp Med 231:235–242

    PubMed  CAS  Google Scholar 

  54. Gruzdeva O, Uchasova E, Belik E, Dyleva Y, Shurygina E, Barbarash O (2014) Lipid, adipokine and ghrelin levels in myocardial infarction patients with insulin resistance. BMC Cardiovasc Disord 14:7

    PubMed  PubMed Central  Google Scholar 

  55. Gruzdeva OV, Karetnikova VN, Akbasheva OE, Fedorova TS, Belik EV, Palicheva EI, Uchasova EG, Dyleva IUA, Brazovskaia NG, Barbarash OL (2013) Lipid, adipokine and ghrelin concentrations in myocardial infarction patients with insulin resistance. Vestn Akad Med Nauk SSSR:13–19

  56. Mao Y, Tokudome T, Otani K, Kishimoto I, Miyazato M, Kangawa K (2013) Excessive sympathoactivation and deteriorated heart function after myocardial infarction in male ghrelin knockout mice. Endocrinology 154:1854–1863

    PubMed  CAS  Google Scholar 

  57. Kondo H, Hojo Y, Takahashi N, Ikemoto T, Aoki H, Dezaki K, Kario K, Katsuki T, Yada T, Shimada K (2010) Roles of ghrelin in left-ventricular remodelling after acute myocardial infarction. Heart Asia 2:1–4

    PubMed  PubMed Central  Google Scholar 

  58. Chang L, Zhao J, Li GZ, Geng B, Pan CS, Qi YF, Tang CS (2004) Ghrelin protects myocardium from isoproterenol-induced injury in rats. Acta Pharmacol Sin 25:1131–1137

    PubMed  CAS  Google Scholar 

  59. Ruozi G, Bortolotti F, Falcione A, Dal Ferro M, Ukovich L, Macedo A, Zentilin L, Filigheddu N, Gortan Cappellari G, Baldini G, Zweyer M, Barazzoni R, Graziani A, Zacchigna S, Giacca M (2015) AAV-mediated in vivo functional selection of tissue-protective factors against ischaemia. Nat Commun 6:7388

    PubMed  CAS  Google Scholar 

  60. Huang CX, Yuan MJ, Huang H, Wu G, Liu Y, Yu SB, Li HT, Wang T (2009) Ghrelin inhibits post-infarct myocardial remodeling and improves cardiac function through anti-inflammation effect. Peptides 30:2286–2291

    PubMed  CAS  Google Scholar 

  61. Yang C, Liu J, Liu K, Du B, Shi K, Ding M, Li B, Yang P (2018) Ghrelin suppresses cardiac fibrosis of post-myocardial infarction heart failure rats by adjusting the activin A-follistatin imbalance. Peptides 99:27–35

    PubMed  Google Scholar 

  62. Wang Q, Sui X, Chen R, Ma PY, Teng YL, Ding T, Sui DJ, Yang P (2018) Ghrelin ameliorates angiotensin II-induced myocardial fibrosis by upregulating peroxisome proliferator-activated receptor gamma in Young male rats. Biomed Res Int 2018:9897581

    PubMed  PubMed Central  Google Scholar 

  63. Eid RA, Alkhateeb MA, Eleawa S, Al-Hashem FH, Al-Shraim M, El-Kott AF, Zaki MSA, Dallak MA, Aldera H (2018) Cardioprotective effect of ghrelin against myocardial infarction-induced left ventricular injury via inhibition of SOCS3 and activation of JAK2/STAT3 signaling. Basic Res Cardiol 113:13

    PubMed  Google Scholar 

  64. Eid RA, Alkhateeb MA, Al-Shraim M, Eleawa SM, Shatoor AS, El-Kott AF, Zaki MSA, Shatoor KA, Bin-Jaliah I, Al-Hashem FH (2019) Ghrelin prevents cardiac cell apoptosis during cardiac remodelling post experimentally induced myocardial infarction in rats via activation of Raf-MEK1/2-ERK1/2 signalling. Arch Physiol Biochem 125:93–103

    PubMed  CAS  Google Scholar 

  65. Wang Q, Lin P, Li P, Feng L, Ren Q, Xie X, Xu J (2017) Ghrelin protects the heart against ischemia/reperfusion injury via inhibition of TLR4/NLRP3 inflammasome pathway. Life Sci 186:50–58

    PubMed  CAS  Google Scholar 

  66. Eid RA, El-Kott AF, Zaki MSA, Eldeen MA, Al-Hashem FH, Alkhateeb MA, Alassiri M, Aldera H (2018) Acylated ghrelin protects aorta damage post-MI via activation of eNOS and inhibition of angiotensin-converting enzyme induced activation of NAD(P)H-dependent oxidase. Ultrastruct Pathol 42:416–429

    PubMed  Google Scholar 

  67. Heineke J, Molkentin JD (2006) Regulation of cardiac hypertrophy by intracellular signalling pathways. Nat Rev Mol Cell Biol 7:589–600

    PubMed  CAS  Google Scholar 

  68. Shimizu I, Minamino T (2016) Physiological and pathological cardiac hypertrophy. J Mol Cell Cardiol 97:245–262

    PubMed  CAS  Google Scholar 

  69. Nakamura M, Sadoshima J (2018) Mechanisms of physiological and pathological cardiac hypertrophy. Nat Rev Cardiol 15:387–407

    PubMed  CAS  Google Scholar 

  70. Wu R, Chaung WW, Dong W, Ji Y, Barrera R, Nicastro J, Molmenti EP, Coppa GF, Wang P (2012) Ghrelin maintains the cardiovascular stability in severe sepsis. J Surg Res 178:370–377

    PubMed  PubMed Central  CAS  Google Scholar 

  71. Soeki T, Koshiba K, Niki T, Kusunose K, Yamaguchi K, Yamada H, Wakatsuki T, Shimabukuro M, Minakuchi K, Kishimoto I, Kangawa K, Sata M (2014) Effect of ghrelin on autonomic activity in healthy volunteers. Peptides 62:1–5

    PubMed  CAS  Google Scholar 

  72. Cauley E, Wang X, Dyavanapalli J, Sun K, Garrott K, Kuzmiak-Glancy S, Kay MW, Mendelowitz D (2015) Neurotransmission to parasympathetic cardiac vagal neurons in the brain stem is altered with left ventricular hypertrophy-induced heart failure. Am J Physiol Heart Circ Physiol 309:H1281–H1287

    PubMed  PubMed Central  CAS  Google Scholar 

  73. Tokudome T, Kangawa K (2019) Physiological significance of ghrelin in the cardiovascular system. Proc Jpn Acad, Ser B, Phys Biol Sci 95:459–467

    CAS  Google Scholar 

  74. Fan D, Takawale A, Lee J, Kassiri Z (2012) Cardiac fibroblasts, fibrosis and extracellular matrix remodeling in heart disease. Fibrogenesis Tissue Repair 5:15

    PubMed  PubMed Central  CAS  Google Scholar 

  75. Pei XM, Yung BY, Yip SP, Ying M, Benzie IF, Siu PM (2014) Desacyl ghrelin prevents doxorubicin-induced myocardial fibrosis and apoptosis via the GHSR-independent pathway. Am J Physiol Endocrinol Metab 306:E311–E323

    PubMed  CAS  Google Scholar 

  76. Wang X, Wang XL, Chen HL, Wu D, Chen JX, Wang XX, Li RL, He JH, Mo L, Cen X, Wei YQ, Jiang W (2014) Ghrelin inhibits doxorubicin cardiotoxicity by inhibiting excessive autophagy through AMPK and p38-MAPK. Biochem Pharmacol 88:334–350

    PubMed  CAS  Google Scholar 

  77. Nichtova Z, Novotova M, Kralova E, Stankovicova T (2012) Morphological and functional characteristics of models of experimental myocardial injury induced by isoproterenol. Gen Physiol Biophys 31:141–151

    PubMed  CAS  Google Scholar 

  78. Li L, Zhang LK, Pang YZ, Pan CS, Qi YF, Chen L, Wang X, Tang CS, Zhang J (2006) Cardioprotective effects of ghrelin and des-octanoyl ghrelin on myocardial injury induced by isoproterenol in rats. Acta Pharmacol Sin 27:527–535

    PubMed  Google Scholar 

  79. Xu X, Ding F, Pang J, Gao X, Xu RK, Hao W, Cao JM, Chen C (2012) Chronic administration of hexarelin attenuates cardiac fibrosis in the spontaneously hypertensive rat. Am J Physiol Heart Circ Physiol 303:H703–H711

    PubMed  CAS  Google Scholar 

  80. Pei XM, Yung BY, Yip SP, Chan LW, Wong CS, Ying M, Siu PM (2015) Protective effects of desacyl ghrelin on diabetic cardiomyopathy. Acta Diabetol 52:293–306

    PubMed  CAS  Google Scholar 

  81. Essick EE, Ouchi N, Wilson RM, Ohashi K, Ghobrial J, Shibata R, Pimentel DR, Sam F (2011) Adiponectin mediates cardioprotection in oxidative stress-induced cardiac myocyte remodeling. Am J Physiol Heart Circ Physiol 301:H984–H993

    PubMed  PubMed Central  CAS  Google Scholar 

  82. Shibata R, Ouchi N, Ito M, Kihara S, Shiojima I, Pimentel DR, Kumada M, Sato K, Schiekofer S, Ohashi K, Funahashi T, Colucci WS, Walsh K (2004) Adiponectin-mediated modulation of hypertrophic signals in the heart. Nat Med 10:1384–1389

    PubMed  PubMed Central  CAS  Google Scholar 

  83. Evans WJ, Morley JE, Argilés J, Bales C, Baracos V, Guttridge D, Jatoi A, Kalantar-Zadeh K, Lochs H, Mantovani G, Marks D, Mitch WE, Muscaritoli M, Najand A, Ponikowski P, Rossi Fanelli F, Schambelan M, Schols A, Schuster M, Thomas D et al (2008) Cachexia: a new definition. Clin Nutr 27:793–799

    PubMed  CAS  Google Scholar 

  84. Levine B, Kalman J, Mayer L, Fillit HM, Packer M (1990) Elevated circulating levels of tumor necrosis factor in severe chronic heart failure. N Engl J Med 323:236–241

    PubMed  CAS  Google Scholar 

  85. Dutka DP, Elborn JS, Delamere F, Shale DJ, Morris GK (1993) Tumour necrosis factor alpha in severe congestive cardiac failure. Br Heart J 70:141–143

    PubMed  PubMed Central  CAS  Google Scholar 

  86. Doehner W, Frenneaux M, Anker SD (2014) Metabolic impairment in heart failure: the myocardial and systemic perspective. J Am Coll Cardiol 64:1388–1400

    PubMed  Google Scholar 

  87. Loncar G, Fülster S, von Haehling S, Popovic V (2013) Metabolism and the heart: an overview of muscle, fat, and bone metabolism in heart failure. Int J Cardiol 162:77–85

    PubMed  Google Scholar 

  88. Bozic B, Loncar G, Prodanovic N, Radojicic Z, Cvorovic V, Dimkovic S, Popovic-Brkic V (2010) Relationship between high circulating adiponectin with bone mineral density and bone metabolism in elderly males with chronic heart failure. J Card Fail 16:301–307

    PubMed  CAS  Google Scholar 

  89. Brink M, Price SR, Chrast J, Bailey JL, Anwar A, Mitch WE, Delafontaine P (2001) Angiotensin II induces skeletal muscle wasting through enhanced protein degradation and down-regulates autocrine insulin-like growth factor I. Endocrinology 142:1489–1496

    PubMed  CAS  Google Scholar 

  90. Muccioli G, Tsch öp M, Papotti M, Deghenghi R, Heiman M, Ghigo E (2002) Neuroendocrine and peripheral activities of ghrelin: implications in metabolism and obesity. Eur J Pharmacol 440:235–254

    PubMed  CAS  Google Scholar 

  91. Schwartz GJ (2000) The role of gastrointestinal vagal afferents in the control of food intake: current prospects. Nutrition 16:866–873

    PubMed  CAS  Google Scholar 

  92. Ueno H, Yamaguchi H, Kangawa K, Nakazato M (2005) Ghrelin: a gastric peptide that regulates food intake and energy homeostasis. Regul Pept 126:11–19

    PubMed  CAS  Google Scholar 

  93. von Haehling S, Anker SD (2015) Treatment of cachexia: an overview of recent developments. Int J Cardiol 184:736–742

    Google Scholar 

  94. Attanasio P, Anker SD, Doehner W, von Haehling S (2011) Hormonal consequences and prognosis of chronic heart failure. Curr Opin Endocrinol Diabetes Obes 18:224–230

    PubMed  CAS  Google Scholar 

  95. Nagaya N, Uematsu M, Kojima M, Date Y, Nakazato M, Okumura H, Hosoda H, Shimizu W, Yamagishi M, Oya H, Koh H, Yutani C, Kangawa K (2001) Elevated circulating level of ghrelin in cachexia associated with chronic heart failure: relationships between ghrelin and anabolic/catabolic factors. Circulation 104:2034–2038

    PubMed  CAS  Google Scholar 

  96. Nagaya N, Kangawa K (2003) Ghrelin improves left ventricular dysfunction and cardiac cachexia in heart failure. Curr Opin Pharmacol 3:146–151

    PubMed  CAS  Google Scholar 

  97. Nagaya N, Kangawa K (2006) Therapeutic potential of ghrelin in the treatment of heart failure. Drugs 66:439–448

    PubMed  CAS  Google Scholar 

  98. Wren AM, Small CJ, Ward HL, Murphy KG, Dakin CL, Taheri S, Kennedy AR, Roberts GH, Morgan DG, Ghatei MA, Bloom SR (2000) The novel hypothalamic peptide ghrelin stimulates food intake and growth hormone secretion. Endocrinology 141:4325–4328

    PubMed  CAS  Google Scholar 

  99. Nakazato M, Murakami N, Date Y, Kojima M, Matsuo H, Kangawa K, Matsukura S (2001) A role for ghrelin in the central regulation of feeding. Nature 409:194–198

    PubMed  CAS  Google Scholar 

  100. Shintani M, Ogawa Y, Ebihara K, Aizawa-Abe M, Miyanaga F, Takaya K, Hayashi T, Inoue G, Hosoda K, Kojima M, Kangawa K, Nakao K (2001) Ghrelin, an endogenous growth hormone secretagogue, is a novel orexigenic peptide that antagonizes leptin action through the activation of hypothalamic neuropeptide Y/Y1 receptor pathway. Diabetes 50:227–232

    PubMed  CAS  Google Scholar 

  101. Palus S, Schur R, Akashi YJ, Bockmeyer B, Datta R, Halem H, Dong J, Culler MD, Adams V, Anker SD, Springer J (2011) Ghrelin and its analogues, BIM-28131 and BIM-28125, improve body weight and regulate the expression of MuRF-1 and MAFbx in a rat heart failure model. PLoS One 6:e26865

    PubMed  PubMed Central  CAS  Google Scholar 

  102. Lenk K, Palus S, Schur R, Datta R, Dong J, Culler MD, Anker S, Springer J, Schuler G, Adams V (2013) Effect of ghrelin and its analogues, BIM-28131 and BIM-28125, on the expression of myostatin in a rat heart failure model. J Cachexia Sarcopenia Muscle 4:63–69

    PubMed  Google Scholar 

  103. Zhang X, Chen C (2012) A new insight of mechanisms, diagnosis and treatment of diabetic cardiomyopathy. Endocrine 41:398–409

    PubMed  CAS  Google Scholar 

  104. Shah S, Thakar CV (2019) Diabetes/kidney/heart disease. Cardiol Clin 37:ix–x

    PubMed  Google Scholar 

  105. Sezai A, Sekino H, Unosawa S, Taoka M, Osaka S, Tanaka M (2019) Canagliflozin for Japanese patients with chronic heart failure and type II diabetes. Cardiovasc Diabetol 18:76

    PubMed  PubMed Central  Google Scholar 

  106. Dei Cas A, Spigoni V, Ridolfi V, Metra M (2013) Diabetes and chronic heart failure: from diabetic cardiomyopathy to therapeutic approach. Endocr Metab Immune Disord Drug Targets, vol 13:38–50

    CAS  Google Scholar 

  107. van Heerebeek L, Hamdani N, Handoko ML, Falcao-Pires I, Musters RJ, Kupreishvili K, Ijsselmuiden AJ, Schalkwijk CG, Bronzwaer JG, Diamant M, Borbely A, van der Velden J, Stienen GJ, Laarman GJ, Niessen HW, Paulus WJ (2008) Diastolic stiffness of the failing diabetic heart: importance of fibrosis, advanced glycation end products, and myocyte resting tension. Circulation 117:43–51

    PubMed  Google Scholar 

  108. Gao WD, Liu Y, Marban E (1996) Selective effects of oxygen free radicals on excitation-contraction coupling in ventricular muscle. Implications for the mechanism of stunned myocardium. Circulation 94:2597–2604

    PubMed  CAS  Google Scholar 

  109. Ma Y, Zhang L, Edwards JN, Launikonis BS, Chen C (2012) Growth hormone secretagogues protect mouse cardiomyocytes from in vitro ischemia/reperfusion injury through regulation of intracellular calcium. PLoS One 7:e35265

    PubMed  PubMed Central  CAS  Google Scholar 

  110. Berti F, Muller E, De Gennaro Colonna V, Rossoni G (1998) Hexarelin exhibits protective activity against cardiac ischaemia in hearts from growth hormone-deficient rats. Growth Hormon IGF Res 8(Suppl B):149–152

    CAS  Google Scholar 

  111. Frascarelli S, Ghelardoni S, Ronca-Testoni S, Zucchi R (2003) Effect of ghrelin and synthetic growth hormone secretagogues in normal and ischemic rat heart. Basic Res Cardiol 98:401–405

    PubMed  CAS  Google Scholar 

  112. Bisi G, Podio V, Valetto MR, Broglio F, Bertuccio G, Del Rio G, Arvat E, Boghen MF, Deghenghi R, Muccioli G, Ong H, Ghigo E (1999) Acute cardiovascular and hormonal effects of GH and hexarelin, a synthetic GH-releasing peptide, in humans. J Endocrinol Investig 22:266–272

    CAS  Google Scholar 

  113. Zhang X, Qu L, Chen L & Chen C 2018, Improvement of cardiomyocyte function by in vivo hexarelin treatment in streptozotocin-induced diabetic rats, Physiol Rep, vol 6

  114. Broglio F, Arvat E, Benso A, Gottero C, Muccioli G, Papotti M, van der Lely AJ, Deghenghi R, Ghigo E (2001) Ghrelin, a natural GH secretagogue produced by the stomach, induces hyperglycemia and reduces insulin secretion in humans. J Clin Endocrinol Metab 86:5083–5086

    PubMed  CAS  Google Scholar 

  115. Lindqvist A, Shcherbina L, Prasad RB, Miskelly MG, Abels M, Martinez-Lopez JA, Fred RG, Nergård BJ, Hedenbro J, Groop L, Hjerling-Leffler J, Wierup N (2020) Ghrelin suppresses insulin secretion in human islets and type 2 diabetes patients have diminished islet ghrelin cell number and lower plasma ghrelin levels. Mol Cell Endocrinol 511:110835

    PubMed  CAS  Google Scholar 

  116. Miegueu P, St Pierre D, Broglio F, Cianflone K (2011) Effect of desacyl ghrelin, obestatin and related peptides on triglyceride storage, metabolism and GHSR signaling in 3T3-L1 adipocytes. J Cell Biochem 112:704–714

    PubMed  CAS  Google Scholar 

  117. Muccioli G, Pons N, Ghe C, Catapano F, Granata R, Ghigo E (2004) Ghrelin and des-acyl ghrelin both inhibit isoproterenol-induced lipolysis in rat adipocytes via a non-type 1a growth hormone secretagogue receptor. Eur J Pharmacol 498:27–35

    PubMed  CAS  Google Scholar 

  118. Rodriguez A, Gomez-Ambrosi J, Catalan V, Gil MJ, Becerril S, Sainz N, Silva C, Salvador J, Colina I, Fruhbeck G (2009) Acylated and desacyl ghrelin stimulate lipid accumulation in human visceral adipocytes. Int J Obes 33(p):541–552

    CAS  Google Scholar 

  119. van der Lely AJ, Tschöp M, Heiman ML, Ghigo E (2004) Biological, physiological, pathophysiological, and pharmacological aspects of ghrelin. Endocr Rev 25:426–457

    PubMed  Google Scholar 

  120. Tesauro M, Schinzari F, Caramanti M, Lauro R, Cardillo C (2010) Cardiovascular and metabolic effects of ghrelin. Curr Diabetes Rev 6:228–235

    PubMed  CAS  Google Scholar 

  121. Aragno M, Mastrocola R, Ghe C, Arnoletti E, Bassino E, Alloatti G, Muccioli G (2012) Obestatin induced recovery of myocardial dysfunction in type 1 diabetic rats: underlying mechanisms. Cardiovasc Diabetol 11:129

    PubMed  PubMed Central  CAS  Google Scholar 

  122. McLaughlin T, Abbasi F, Lamendola C, Frayo RS, Cummings DE (2004) Plasma ghrelin concentrations are decreased in insulin-resistant obese adults relative to equally obese insulin-sensitive controls. J Clin Endocrinol Metab 89:1630–1635

    PubMed  CAS  Google Scholar 

  123. Tesauro M, Schinzari F, Iantorno M, Rizza S, Melina D, Lauro D, Cardillo C (2005) Ghrelin improves endothelial function in patients with metabolic syndrome. Circulation 112:2986–2992

    PubMed  CAS  Google Scholar 

  124. Gauna C, Meyler FM, Janssen JA, Delhanty PJ, Abribat T, van Koetsveld P, Hofland LJ, Broglio F, Ghigo E, van der Lely AJ (2004) Administration of acylated ghrelin reduces insulin sensitivity, whereas the combination of acylated plus unacylated ghrelin strongly improves insulin sensitivity. J Clin Endocrinol Metab 89:5035–5042

    PubMed  CAS  Google Scholar 

  125. Giles TD, Materson BJ, Cohn JN, Kostis JB (2009) Definition and classification of hypertension: an update. J Clin Hypertens (Greenwich) 11:611–614

    Google Scholar 

  126. Poykko SM, Kellokoski E, Horkko S, Kauma H, Kesaniemi YA, Ukkola O (2003) Low plasma ghrelin is associated with insulin resistance, hypertension, and the prevalence of type 2 diabetes. Diabetes 52:2546–2553

    PubMed  Google Scholar 

  127. Poykko S, Ukkola O, Kauma H, Savolainen MJ, Kesaniemi YA (2003) Ghrelin Arg51Gln mutation is a risk factor for type 2 diabetes and hypertension in a random sample of middle-aged subjects. Diabetologia 46:455–458

    PubMed  CAS  Google Scholar 

  128. Yang D, Liu Z, Yang Z (2013) Ghrelin and its relation with N-terminal brain natriuretic peptide, endothelin-1 and nitric oxide in patients with idiopathic pulmonary hypertension. Cardiology 124:241–245

    PubMed  CAS  Google Scholar 

  129. Lin Y, Matsumura K, Fukuhara M, Kagiyama S, Fujii K, Iida M (2004) Ghrelin acts at the nucleus of the solitary tract to decrease arterial pressure in rats. Hypertension 43:977–982

    PubMed  CAS  Google Scholar 

  130. Henriques-Coelho T, Correia-Pinto J, Roncon-Albuquerque R, Baptista MJ, Lourenco AP, Oliveira SM, Brandao-Nogueira A, Teles A, Fortunato JM, Leite-Moreira AF (2004) Endogenous production of ghrelin and beneficial effects of its exogenous administration in monocrotaline-induced pulmonary hypertension. Am J Physiol Heart Circ Physiol 287:H2885–H2890

    PubMed  CAS  Google Scholar 

  131. Makino Y, Hosoda H, Shibata K, Makino I, Kojima M, Kangawa K, Kawarabayashi T (2002) Alteration of plasma ghrelin levels associated with the blood pressure in pregnancy. Hypertension 39:781–784

    PubMed  CAS  Google Scholar 

  132. Raso GM, Bianco G, Iacono A, Esposito E, Autore G, Ferrante MC, Calignano A, Meli R (2007) Maternal adaptations to pregnancy in spontaneously hypertensive rats: leptin and ghrelin evaluation. J Endocrinol 194:611–619

    PubMed  CAS  Google Scholar 

  133. Kalogeris T, Baines CP, Krenz M, Korthuis RJ (2012) Cell biology of ischemia/reperfusion injury. Int Rev Cell Mol Biol 298:229–317

    PubMed  PubMed Central  CAS  Google Scholar 

  134. Mao Y, Tokudome T, Kishimoto I (2014) The cardiovascular action of hexarelin. J Geriatr Cardiol, vol 11:253–258

    Google Scholar 

  135. Ferdinandy P, Hausenloy DJ, Heusch G, Baxter GF, Schulz R (2014) Interaction of risk factors, comorbidities, and comedications with ischemia/reperfusion injury and cardioprotection by preconditioning, postconditioning, and remote conditioning. Pharmacol Rev 66:1142–1174

    PubMed  CAS  Google Scholar 

  136. Raghay K, Akki R, Bensaid D, Errami M (2020) Ghrelin as an anti-inflammatory and protective agent in ischemia/reperfusion injury. Peptides 124:170226

    PubMed  CAS  Google Scholar 

  137. Bukowczan J, Warzecha Z, Ceranowicz P, Kusnierz-Cabala B, Tomaszewska R, Dembinski A (2015) Therapeutic effect of ghrelin in the course of ischemia/reperfusion-induced acute pancreatitis. Curr Pharm Des 21:2284–2290

    PubMed  CAS  Google Scholar 

  138. Qin Y, Li Z, Wang Z, Li Y, Zhao J, Mulholland M, Zhang W (2014) Ghrelin contributes to protection of hepatocellular injury induced by ischaemia/reperfusion. Liver Int 34:567–575

    PubMed  CAS  Google Scholar 

  139. Zhang H, Cui Z, Luo G, Zhang J, Ma T, Hu N, Cui T (2013) Ghrelin attenuates intestinal ischemia/reperfusion injury in mice by activating the mTOR signaling pathway. Int J Mol Med 32:851–859

    PubMed  CAS  Google Scholar 

  140. Zhang Q, Huang C, Meng B, Tang T, Shi Q, Yang H (2012) Acute effect of ghrelin on ischemia/reperfusion injury in the rat spinal cord. Int J Mol Sci 13:9864–9876

    PubMed  PubMed Central  CAS  Google Scholar 

  141. Rajan D, Wu R, Shah KG, Jacob A, Coppa GF, Wang P (2012) Human ghrelin protects animals from renal ischemia-reperfusion injury through the vagus nerve. Surgery 151:37–47

    PubMed  Google Scholar 

  142. Ma Y, Zhang L, Launikonis BS, Chen C (2012) Growth hormone secretagogues preserve the electrophysiological properties of mouse cardiomyocytes isolated from in vitro ischemia/reperfusion heart. Endocrinology 153:5480–5490

    PubMed  CAS  Google Scholar 

  143. Zhang GG, Cai HQ, Li YH, Sui YB, Zhang JS, Chang JR, Ning M, Wu Y, Tang CS, Qi YF, Yin XH (2013) Ghrelin protects heart against ERS-induced injury and apoptosis by activating AMP-activated protein kinase. Peptides 48:156–165

    PubMed  CAS  Google Scholar 

  144. Yuan MJ, Huang H, Tang YH, Wu G, Gu YW, Chen YJ, Huang CX (2011) Effects of ghrelin on Cx43 regulation and electrical remodeling after myocardial infarction in rats. Peptides 32:2357–2361

    PubMed  CAS  Google Scholar 

  145. Soeki T, Niki T, Uematsu E, Bando S, Matsuura T, Kusunose K, Ise T, Ueda Y, Tomita N, Yamaguchi K, Koshiba K, Yagi S, Fukuda D, Taketani Y, Iwase T, Yamada H, Wakatsuki T, Akaike M, Shimabukuro M, Kishimoto I et al (2013) Ghrelin protects the heart against ischemia-induced arrhythmias by preserving connexin-43 protein. Heart Vessel 28:795–801

    Google Scholar 

  146. Camargo-Silva G, Turones LC, da Cruz KR, Gomes KP, Mendonça MM, Nunes A, de Jesus IG, Colugnati DB, Pansani AP, Pobbe RLH, Santos R, Fontes MAP, Guatimosim S, de Castro CH, Ianzer D, Ferreira RN, Xavier CH (2018) Ghrelin potentiates cardiac reactivity to stress by modulating sympathetic control and beta-adrenergic response. Life Sci 196:84–92

    PubMed  CAS  Google Scholar 

  147. Sun HJ, Wu ZY, Nie XW, Bian JS (2019) Role of endothelial dysfunction in cardiovascular diseases: the link between inflammation and hydrogen sulfide. Front Pharmacol 10:1568

    PubMed  CAS  Google Scholar 

  148. Shiiya T, Nakazato M, Mizuta M, Date Y, Mondal MS, Tanaka M, Nozoe S, Hosoda H, Kangawa K, Matsukura S (2002) Plasma ghrelin levels in lean and obese humans and the effect of glucose on ghrelin secretion. J Clin Endocrinol Metab 87:240–244

    CAS  PubMed  Google Scholar 

  149. Nagaya N, Kojima M, Uematsu M, Yamagishi M, Hosoda H, Oya H, Hayashi Y, Kangawa K (2001) Hemodynamic and hormonal effects of human ghrelin in healthy volunteers. Am J Phys Regul Integr Comp Phys 280:R1483–R1487

    CAS  Google Scholar 

  150. Flammer AJ, Anderson T, Celermajer DS, Creager MA, Deanfield J, Ganz P, Hamburg NM, Lüscher TF, Shechter M, Taddei S, Vita JA, Lerman A (2012) The assessment of endothelial function: from research into clinical practice. Circulation 126:753–767

    PubMed  PubMed Central  Google Scholar 

  151. Matsumura K, Tsuchihashi T, Fujii K, Abe I, Iida M (2002) Central ghrelin modulates sympathetic activity in conscious rabbits. Hypertension 40:694–699

    PubMed  CAS  Google Scholar 

  152. Okumura H, Nagaya N, Enomoto M, Nakagawa E, Oya H, Kangawa K (2002) Vasodilatory effect of ghrelin, an endogenous peptide from the stomach. J Cardiovasc Pharmacol 39:779–783

    PubMed  CAS  Google Scholar 

  153. Wiley KE, Davenport AP (2002) Comparison of vasodilators in human internal mammary artery: ghrelin is a potent physiological antagonist of endothelin-1. Br J Pharmacol 136:1146–1152

    PubMed  PubMed Central  CAS  Google Scholar 

  154. Iantorno M, Chen H, Kim JA, Tesauro M, Lauro D, Cardillo C, Quon MJ (2007) Ghrelin has novel vascular actions that mimic PI 3-kinase-dependent actions of insulin to stimulate production of NO from endothelial cells. Am J Physiol Endocrinol Metab 292:E756–E764

    PubMed  CAS  Google Scholar 

  155. Shimizu Y, Nagaya N, Teranishi Y, Imazu M, Yamamoto H, Shokawa T, Kangawa K, Kohno N, Yoshizumi M (2003) Ghrelin improves endothelial dysfunction through growth hormone-independent mechanisms in rats. Biochem Biophys Res Commun 310:830–835

    PubMed  CAS  Google Scholar 

  156. Kadoglou NP, Sailer N, Moumtzouoglou A, Kapelouzou A, Tsanikidis H, Vitta I, Karkos C, Karayannacos PE, Gerasimidis T, Liapis CD (2010) Visfatin (nampt) and ghrelin as novel markers of carotid atherosclerosis in patients with type 2 diabetes. Exp Clin Endocrinol Diabetes 118:75–80

    PubMed  CAS  Google Scholar 

  157. Kotani K, Sakane N, Saiga K, Adachi S, Mu H, Kurozawa Y, Kawano M (2006) Serum ghrelin and carotid atherosclerosis in older Japanese people with metabolic syndrome. Arch Med Res 37:903–906

    PubMed  CAS  Google Scholar 

  158. Yano Y, Toshinai K, Inokuchi T, Kangawa K, Shimada K, Kario K, Nakazato M (2009) Plasma des-acyl ghrelin, but not plasma HMW adiponectin, is a useful cardiometabolic marker for predicting atherosclerosis in elderly hypertensive patients. Atherosclerosis 204:590–594

    PubMed  CAS  Google Scholar 

  159. Zhang M, Fang WY, Yuan F, Qu XK, Liu H, Xu YJ, Chen H, Yu YF, Shen Y, Zheng ZC (2012) Plasma ghrelin levels are closely associated with severity and morphology of angiographically-detected coronary atherosclerosis in Chineses patients with diabetes mellitus. Acta Pharmacol Sin 33:452–458

    PubMed  PubMed Central  CAS  Google Scholar 

  160. Poykko SM, Kellokoski E, Ukkola O, Kauma H, Paivansalo M, Kesaniemi YA, Horkko S (2006) Plasma ghrelin concentrations are positively associated with carotid artery atherosclerosis in males. J Intern Med 260:43–52

    PubMed  CAS  Google Scholar 

  161. Kim SJ, Paik KH, Kim DI, Choe YH, Kim SW, Jin DK (2010) Correlation between hyperghrelinemia and carotid artery intima-media thickness in children with Prader-Willi syndrome. Yonsei Med J 51:339–344

    PubMed  PubMed Central  Google Scholar 

  162. Laurila M, Santaniemi M, Kesäniemi YA, Ukkola O (2014) High plasma ghrelin protects from coronary heart disease and Leu72Leu polymorphism of ghrelin gene from cancer in healthy adults during the 19 years follow-up study. Peptides 61:122–129

    PubMed  CAS  Google Scholar 

  163. Tahergorabi Z, Rashidi B, Khazaei M (2013) Ghrelin does not alter aortic intima-media thickness and adipose tissue characteristics in control and obese mice. Iran J Basic Med Sci, vol 16:942–945

    Google Scholar 

  164. Ai W, Wu M, Chen L, Jiang B, Mu M, Liu L, Yuan Z (2017) Ghrelin ameliorates atherosclerosis by inhibiting endoplasmic reticulum stress. Fundam Clin Pharmacol 31:147–154

    PubMed  CAS  Google Scholar 

  165. Togliatto G, Trombetta A, Dentelli P, Gallo S, Rosso A, Cotogni P, Granata R, Falcioni R, Delale T, Ghigo E, Brizzi MF (2015) Unacylated ghrelin induces oxidative stress resistance in a glucose intolerance and peripheral artery disease mouse model by restoring endothelial cell miR-126 expression. Diabetes 64:1370–1382

    PubMed  CAS  Google Scholar 

  166. Zhang M, Qu X, Yuan F, Yang Y, Xu L, Dai J, Wang W, Fei J, Hou X, Fang W (2015) Ghrelin receptor deficiency aggravates atherosclerotic plaque instability. Front Biosci (Landmark Ed) 20:604–613

    CAS  Google Scholar 

  167. Zhang M, Yuan F, Chen H, Qiu X, Fang W (2007) Effect of exogenous ghrelin on cell differentiation antigen 40 expression in endothelial cells. Acta Biochim Biophys Sin Shanghai 39:974–981

    PubMed  CAS  Google Scholar 

  168. Li WG, Gavrila D, Liu X, Wang L, Gunnlaugsson S, Stoll LL, McCormick ML, Sigmund CD, Tang C, Weintraub NL (2004) Ghrelin inhibits proinflammatory responses and nuclear factor-kappaB activation in human endothelial cells. Circulation 109:2221–2226

    PubMed  CAS  Google Scholar 

  169. Genis BB, Granada ML, Alonso N, Lauzurica R, Jimenez JA, Barluenga E, Homs M, Pastor MC, Salinas I, Quintero JC, Sanmarti A, Romero R (2007) Ghrelin, glucose homeostasis, and carotid intima media thickness in kidney transplantation. Transplantation 84:1248–1254

    PubMed  CAS  Google Scholar 

  170. Wang L, Chen Q, Li G, Ke D (2012) Ghrelin stimulates angiogenesis via GHSR1a-dependent MEK/ERK and PI3K/Akt signal pathways in rat cardiac microvascular endothelial cells. Peptides 33:92–100

    PubMed  Google Scholar 

  171. Yuan M-J, Hu H-Y, Huang C-X et al (2012) Myocardial angiogenesis after chronic ghrelin treatment in a rat myocardial infarction model. Regul Pept 179:39–42

    PubMed  CAS  Google Scholar 

  172. Wang L, Chen Q, Li G, Ke D (2015) Ghrelin ameliorates impaired angiogenesis of ischemic myocardium through GHSR1a-mediated AMPK/eNOS signal pathway in diabetic rats. Peptides 73:77–87

    PubMed  Google Scholar 

  173. Katare R, Rawal S, Munasinghe PE, Tsuchimochi H, Inagaki T, Fujii Y, Dixit P, Umetani K, Kangawa K, Shirai M, Schwenke DO (2016) Ghrelin promotes functional angiogenesis in a mouse model of critical limb ischemia through activation of proangiogenic microRNAs. Endocrinology 157:432–445

    PubMed  Google Scholar 

  174. Fish JE, Santoro MM, Morton SU, Yu S, Yeh RF, Wythe JD, Ivey KN, Bruneau BG, Stainier DY, Srivastava D (2008) miR-126 regulates angiogenic signaling and vascular integrity. Dev Cell 15:272–284

    PubMed  PubMed Central  CAS  Google Scholar 

  175. Wang J, He L, Huwatibieke B, Liu L, Lan H, Zhao J, Li Y, Zhang W (2018) Ghrelin stimulates endothelial cells angiogenesis through extracellular regulated protein kinases (ERK) signaling pathway. Int J Mol Sci 19:2530

    PubMed Central  Google Scholar 

  176. Mayo LD, Kessler KM, Pincheira R, Warren RS, Donner DB (2001) Vascular endothelial cell growth factor activates CRE-binding protein by signaling through the KDR receptor tyrosine kinase. J Biol Chem 276:25184–25189

    PubMed  CAS  Google Scholar 

  177. Tahergorabi Z, Rashidi B, Khazaei M (2013) Ghrelin does not modulate angiogenesis in matrigel plug in normal and diet-induced obese mice. J Res Med Sci 18:939–942

    PubMed  PubMed Central  CAS  Google Scholar 

  178. Tahergorabi Z, Khazaei M, Rashidi B (2015) Systemic administration of ghrelin did not restore angiogenesis in hindlimb ischemia in control and diet-induced obese mice. Bratisl Lek Listy 116:35–40

    PubMed  CAS  Google Scholar 

  179. Khazaei M, Tahergorabi Z (2017) Ghrelin did not change coronary angiogenesis in diet-induced obese mice. Cell Mol Biol (Noisy-le-grand) 63:96–99

    CAS  Google Scholar 

  180. Anand S, Majeti BK, Acevedo LM, Murphy EA, Mukthavaram R, Scheppke L, Huang M, Shields DJ, Lindquist JN, Lapinski PE, King PD, Weis SM, Cheresh DA (2010) MicroRNA-132-mediated loss of p120RasGAP activates the endothelium to facilitate pathological angiogenesis. Nat Med 16:909–914

    PubMed  PubMed Central  CAS  Google Scholar 

  181. Jin W, Reddy MA, Chen Z, Putta S, Lanting L, Kato M, Park JT, Chandra M, Wang C, Tangirala RK, Natarajan R (2012) Small RNA sequencing reveals microRNAs that modulate angiotensin II effects in vascular smooth muscle cells. J Biol Chem 287:15672–15683

    PubMed  PubMed Central  CAS  Google Scholar 

  182. Hansen GN, Hansen BL, Jørgensen PN, Scharrer B (1990) Immunocytochemical localization and immunochemical characterization of an insulin-related peptide in the insect Leucophaea maderae. Cell Tissue Res 259:265–273

    PubMed  CAS  Google Scholar 

  183. Stahlhut C, Suárez Y, Lu J, Mishima Y, Giraldez AJ (2012) miR-1 and miR-206 regulate angiogenesis by modulating VegfA expression in zebrafish. Development 139:4356–4364

    PubMed  PubMed Central  CAS  Google Scholar 

  184. Stenzel D, Lundkvist A, Sauvaget D, Busse M, Graupera M, van der Flier A, Wijelath ES, Murray J, Sobel M, Costell M, Takahashi S, F ässler R, Yamaguchi Y, Gutmann DH, Hynes RO, Gerhardt H (2011) Integrin-dependent and -independent functions of astrocytic fibronectin in retinal angiogenesis. Development 138:4451–4463

    PubMed  PubMed Central  CAS  Google Scholar 

  185. Tsutsui H, Tsuchihashi-Makaya M, Kinugawa S, Goto D, Takeshita A (2007) Characteristics and outcomes of patients with heart failure in general practices and hospitals. Circ J 71:449–454

    PubMed  Google Scholar 

  186. Rosamond W, Flegal K, Furie K, Go A, Greenlund K, Haase N, Hailpern SM, Ho M, Howard V, Kissela B, Kissela B, Kittner S, Lloyd-Jones D, McDermott M, Meigs J, Moy C, Nichol G, ODonnell C, Roger V, Sorlie P et al (2008) Heart disease and stroke statistics–2008 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 117:25–146

    Google Scholar 

  187. Zhang G, Yin X, Qi Y, Pendyala L, Chen J, Hou D, Tang C (2010) Ghrelin and cardiovascular diseases. Curr Cardiol Rev 6:62–70

    PubMed  PubMed Central  CAS  Google Scholar 

  188. Mao Y, Tokudome T, Kishimoto I (2014) Ghrelin as a treatment for cardiovascular diseases. Hypertension 64:450–454

    PubMed  CAS  Google Scholar 

  189. Nagaya N, Miyatake K, Uematsu M, Oya H, Shimizu W, Hosoda H, Kojima M, Nakanishi N, Mori H, Kangawa K (2001) Hemodynamic, renal, and hormonal effects of ghrelin infusion in patients with chronic heart failure. J Clin Endocrinol Metab 86:5854–5859

    PubMed  CAS  Google Scholar 

  190. Ashby D, Choi P, Bloom S (2008) Gut hormones and the treatment of disease cachexia. Proc Nutr Soc 67:263–269

    PubMed  CAS  Google Scholar 

  191. Xin X, Ren AJ, Zheng X, Qin YW, Zhao XX, Yuan WJ, Guo ZF (2009) Disturbance of circulating ghrelin and obestatin in chronic heart failure patients especially in those with cachexia. Peptides 30:2281–2285

    PubMed  CAS  Google Scholar 

  192. Mitacchione G, Powers JC, Grifoni G, Woitek F, Lam A, Ly L, Settanni F, Makarewich CA, McCormick R, Trovato L, Houser SR, Granata R, Recchia FA (2014) The gut hormone ghrelin partially reverses energy substrate metabolic alterations in the failing heart. Circ Heart Fail 7:643–651

    PubMed  PubMed Central  CAS  Google Scholar 

  193. Enomoto M, Nagaya N, Uematsu M, Okumura H, Nakagawa E, Ono F, Hosoda H, Oya H, Kojima M, Kanmatsuse K, Kangawa K (2003) Cardiovascular and hormonal effects of subcutaneous administration of ghrelin, a novel growth hormone-releasing peptide, in healthy humans. Clin Sci 105:431–435

    CAS  Google Scholar 

  194. Schiattarella GG, Hill JA (2016) Therapeutic targeting of autophagy in cardiovascular disease. J Mol Cell Cardiol 95:86–93

    PubMed  CAS  Google Scholar 

  195. Sciarretta S, Maejima Y, Zablocki D, Sadoshima J (2018) The role of autophagy in the heart. Annu Rev Physiol 80:1–26

    PubMed  CAS  Google Scholar 

  196. Xu M, Liu L, Song C, Chen W, Gui S (2017) Ghrelin improves vascular autophagy in rats with vascular calcification. Life Sci 179:23–29

    PubMed  CAS  Google Scholar 

  197. Godar RJ, Ma X, Liu H, Murphy JT, Weinheimer CJ, Kovacs A, Crosby SD, Saftig P, Diwan A (2015) Repetitive stimulation of autophagy-lysosome machinery by intermittent fasting preconditions the myocardium to ischemia-reperfusion injury. Autophagy 11:1537–1560

    PubMed  PubMed Central  CAS  Google Scholar 

  198. Zhang S, Mao Y, Fan X (2018) Inhibition of ghrelin o-acyltransferase attenuated lipotoxicity by inducing autophagy via AMPK-mTOR pathway. Drug Des Devel Ther 12:873–885

    PubMed  PubMed Central  CAS  Google Scholar 

  199. Mao Y, Cheng J, Yu F, Li H, Guo C, Fan X (2015) Ghrelin attenuated lipotoxicity via autophagy induction and nuclear factor-κB inhibition. Cell Physiol Biochem 37:563–576

    PubMed  CAS  Google Scholar 

  200. Yuan MJ, Wang T (2020) The new mechanism of ghrelin/GHSR-1a on autophagy regulation. Peptides, vol 126:170264

    CAS  Google Scholar 

  201. Andres AM, Kooren JA, Parker SJ, Tucker KC, Ravindran N, Ito BR, Huang C, Venkatraman V, Van Eyk JE, Gottlieb RA, Mentzer RM (2016) Discordant signaling and autophagy response to fasting in hearts of obese mice: implications for ischemia tolerance. Am J Physiol Heart Circ Physiol 311:H219–H228

    PubMed  PubMed Central  Google Scholar 

  202. Toshinai K, Mondal MS, Nakazato M, Date Y, Murakami N, Kojima M, Kangawa K, Matsukura S (2001) Upregulation of ghrelin expression in the stomach upon fasting, insulin-induced hypoglycemia, and leptin administration. Biochem Biophys Res Commun 281:1220–1225

    PubMed  CAS  Google Scholar 

  203. Agbo E, Li MX, Wang YQ, Saahene RO, Massaro J, Tian GZ (2019) Hexarelin protects cardiac H9C2 cells from angiotensin II-induced hypertrophy via the regulation of autophagy. Pharmazie 74:485–491

    PubMed  CAS  Google Scholar 

  204. Tong XX, Wu D, Wang X, Chen HL, Chen JX, Wang XX, Wang XL, Gan L, Guo ZY, Shi GX, Zhang YZ, Jiang W (2012) Ghrelin protects against cobalt chloride-induced hypoxic injury in cardiac H9c2 cells by inhibiting oxidative stress and inducing autophagy. Peptides 38:217–227

    PubMed  CAS  Google Scholar 

  205. Kola B, Hubina E, Tucci SA, Kirkham TC, Garcia EA, Mitchell SE, Williams LM, Hawley SA, Hardie DG, Grossman AB, Korbonits M (2005) Cannabinoids and ghrelin have both central and peripheral metabolic and cardiac effects via AMP-activated protein kinase. J Biol Chem 280:25196–25201

    PubMed  CAS  Google Scholar 

  206. Mihaylova MM, Shaw RJ (2011) The AMPK signalling pathway coordinates cell growth, autophagy and metabolism. Nat Cell Biol 13:1016–1023

    PubMed  PubMed Central  CAS  Google Scholar 

  207. Sun Q, Zang WJ, Chen C (2010) Growth hormone secretagogues reduce transient outward K+ current via phospholipase C/protein kinase C signaling pathway in rat ventricular myocytes. Endocrinology 151:1228–1235

    PubMed  CAS  Google Scholar 

  208. Bedendi I, Alloatti G, Marcantoni A, Malan D, Catapano F, Ghe C, Deghenghi R, Ghigo E, Muccioli G (2003) Cardiac effects of ghrelin and its endogenous derivatives des-octanoyl ghrelin and des-Gln14-ghrelin. Eur J Pharmacol 476:87–95

    PubMed  CAS  Google Scholar 

  209. Bedendi I, Gallo MP, Malan D, Levi RC, Alloatti G (2001) Role of endothelial cells in modulation of contractility induced by hexarelin in rat ventricle. Life Sci 69:2189–2201

    PubMed  CAS  Google Scholar 

  210. Cao CM, Xia Q, Gao Q, Chen M, Wong TM (2005) Calcium-activated potassium channel triggers cardioprotection of ischemic preconditioning. J Pharmacol Exp Ther 312:644–650

    PubMed  CAS  Google Scholar 

  211. Xu W, Liu Y, Wang S, McDonald T, Van Eyk JE, Sidor A, ORourke B (2002) Cytoprotective role of Ca2+- activated K+ channels in the cardiac inner mitochondrial membrane. Science 298:1029–1033

    PubMed  CAS  Google Scholar 

  212. Xu Y, Tuteja D, Zhang Z, Xu D, Zhang Y, Rodriguez J, Nie L, Tuxson HR, Young JN, Glatter KA, Vázquez AE, Yamoah EN, Chiamvimonvat N (2003) Molecular identification and functional roles of a Ca(2+)-activated K+ channel in human and mouse hearts. J Biol Chem 278:49085–49094

    PubMed  CAS  Google Scholar 

  213. Casis O, Iriarte M, Gallego M, Sanchez-Chapula JA (1998) Differences in regional distribution of K+ current densities in rat ventricle. Life Sci 63:391–400

    PubMed  CAS  Google Scholar 

  214. Greenstein JL, Wu R, Po S, Tomaselli GF, Winslow RL (2000) Role of the calcium-independent transient outward current I(to1) in shaping action potential morphology and duration. Circ Res 87:1026–1033

    PubMed  CAS  Google Scholar 

  215. Xu XB, Cao JM, Pang JJ, Xu RK, Ni C, Zhu WL, Asotra K, Chen MC, Chen C (2003) The positive inotropic and calcium-mobilizing effects of growth hormone-releasing peptides on rat heart. Endocrinology 144:5050–5057

    PubMed  CAS  Google Scholar 

  216. Soares JB, Rocha-Sousa A, Castro-Chaves P, Henriques-Coelho T, Leite-Moreira AF (2006) Inotropic and lusitropic effects of ghrelin and their modulation by the endocardial endothelium, NO, prostaglandins, GHS-R1a and KCa channels. Peptides 27:1616–1623

    PubMed  CAS  Google Scholar 

  217. Soares JB, Rocha-Sousa A, Castro-Chaves P, Henriques-Coelho T, Lourenco AP, Roncon-Albuquerque R, Leite-Moreira AF (2005) Contractile effects of ghrelin and expression of its receptor GHS-R1a in normal and hypertrophic myocardium. Rev Port Cardiol 24:1235–1242

    PubMed  Google Scholar 

  218. Mustafa ER, Lopez Soto EJ, Martinez Damonte V, Rodriguez SS, Lipscombe D, Raingo J (2017) Constitutive activity of the ghrelin receptor reduces surface expression of voltage-gated Ca2+ channels in a CaVβ-dependent manner. J Cell Sci 130:3907–3917

    PubMed  PubMed Central  CAS  Google Scholar 

  219. Warbrick I, Rabkin SW (2019) Effect of the peptides relaxin, neuregulin, ghrelin and glucagon-like peptide-1, on cardiomyocyte factors involved in the molecular mechanisms leading to diastolic dysfunction and/or heart failure with preserved ejection fraction. Peptides 111:33–41

    PubMed  CAS  Google Scholar 

  220. Sun Q, Ma Y, Zhang L, Zhao YF, Zang WJ, Chen C (2010) Effects of GH secretagogues on contractility and Ca2+ homeostasis of isolated adult rat ventricular myocytes. Endocrinology 151:4446–4454

    PubMed  CAS  Google Scholar 

  221. Pettersson I, Muccioli G, Granata R, Deghenghi R, Ghigo E, Ohlsson C, Isgaard J (2002) Natural (ghrelin) and synthetic (hexarelin) GH secretagogues stimulate H9c2 cardiomyocyte cell proliferation. J Endocrinol 175:201–209

    PubMed  CAS  Google Scholar 

  222. Pierno S, De Luca A, Desaphy JF, Fraysse B, Liantonio A, Didonna MP, Lograno M, Cocchi D, Smith RG, Camerino DC (2003) Growth hormone secretagogues modulate the electrical and contractile properties of rat skeletal muscle through a ghrelin-specific receptor. Br J Pharmacol 139:575–584

    PubMed  PubMed Central  CAS  Google Scholar 

  223. Shinde UA, Desai KM, Yu C, Gopalakrishnan V (2005) Nitric oxide synthase inhibition exaggerates the hypotensive response to ghrelin: role of calcium-activated potassium channels. J Hypertens 23:779–784

    PubMed  CAS  Google Scholar 

  224. Granata R, Settanni F, Biancone L, Trovato L, Nano R, Bertuzzi F, Destefanis S, Annunziata M, Martinetti M, Catapano F, Ghè C, Isgaard J, Papotti M, Ghigo E, Muccioli G (2007) Acylated and unacylated ghrelin promote proliferation and inhibit apoptosis of pancreatic beta-cells and human islets: involvement of 3,5-cyclic adenosine monophosphate/protein kinase A, extracellular signal-regulated kinase 1/2, and phosphatidyl inositol 3-kinase/Akt signaling. Endocrinology 148:512–529

    PubMed  CAS  Google Scholar 

  225. Iglesias MJ, Pineiro R, Blanco M, Gallego R, Dieguez C, Gualillo O, Gonzalez-Juanatey JR, Lago F (2004) Growth hormone releasing peptide (ghrelin) is synthesized and secreted by cardiomyocytes. Cardiovasc Res 62:481–488

    PubMed  CAS  Google Scholar 

  226. Shati AA, El-Kott AF (2019) Acylated ghrelin prevents doxorubicin-induced cardiac intrinsic cell death and fibrosis in rats by restoring IL-6/JAK2/STAT3 signaling pathway and inhibition of STAT1. Naunyn Schmiedeberg's Arch Pharmacol 392(p):1151–1168

    CAS  Google Scholar 

  227. Xu Z, Lin S, Wu W, Tan H, Wang Z, Cheng C, Lu L, Zhang X (2008) Ghrelin prevents doxorubicin-induced cardiotoxicity through TNF-alpha/NF-kappaB pathways and mitochondrial protective mechanisms. Toxicology 247:133–138

    PubMed  CAS  Google Scholar 

  228. Gupta S, Kass GE, Szegezdi E, Joseph B (2009) The mitochondrial death pathway: a promising therapeutic target in diseases. J Cell Mol Med 13:1004–1033

    PubMed  PubMed Central  CAS  Google Scholar 

  229. Zhang GG, Teng X, Liu Y, Cai Y, Zhou YB, Duan XH, Song JQ, Shi Y, Tang CS, Yin XH, Qi YF (2009) Inhibition of endoplasm reticulum stress by ghrelin protects against ischemia/reperfusion injury in rat heart. Peptides 30:1109–1116

    PubMed  CAS  Google Scholar 

  230. Melnikova NP, Timoshin SS, Jivotova EY, Pelliniemi LJ, Jokinen E, Abdelwahid E (2006) Angiotensin-II activates apoptosis, proliferation and protein synthesis in the left heart ventricle of newborn albino rats. Int J Cardiol 112:219–222

    Google Scholar 

  231. Alloatti G, Arnoletti E, Bassino E, Penna C, Perrelli MG, Ghé C, Muccioli G (2010) Obestatin affords cardioprotection to the ischemic-reperfused isolated rat heart and inhibits apoptosis in cultures of similarly stressed cardiomyocytes. Am J Physiol Heart Circ Physiol 299:H470–H481

    PubMed  CAS  Google Scholar 

  232. Wang X, Yang C, Liu X, Yang P (2018) Ghrelin alleviates angiotensin II-induced H9c2 apoptosis: impact of the miR-208 family. Med Sci Monit 24:6707–6716

    PubMed  PubMed Central  CAS  Google Scholar 

  233. Dixit VD, Schaffer EM, Pyle RS, Collins GD, Sakthivel SK, Palaniappan R, Lillard JW, Taub DD (2004) Ghrelin inhibits leptin- and activation-induced proinflammatory cytokine expression by human monocytes and T cells. J Clin Invest 114:57–66

    PubMed  PubMed Central  CAS  Google Scholar 

  234. Wang L, Saint-Pierre DH, Taché Y (2002) Peripheral ghrelin selectively increases Fos expression in neuropeptide Y - synthesizing neurons in mouse hypothalamic arcuate nucleus. Neurosci Lett 325:47–51

    PubMed  CAS  Google Scholar 

  235. Banks WA, Tschöp M, Robinson SM, Heiman ML (2002) Extent and direction of ghrelin transport across the blood-brain barrier is determined by its unique primary structure. J Pharmacol Exp Ther 302:822–827

    PubMed  CAS  Google Scholar 

  236. Tsubota Y, Owada-Makabe K, Yukawa K, Maeda M (2005) Hypotensive effect of des-acyl ghrelin at nucleus tractus solitarii of rat. Neuroreport 16:163–166

    PubMed  CAS  Google Scholar 

  237. Vlasova MA, Järvinen K, Herzig KH (2009) Cardiovascular effects of ghrelin antagonist in conscious rats. Regul Pept 156:72–76

    PubMed  CAS  Google Scholar 

  238. Shimizu S, Akiyama T, Kawada T, Sonobe T, Kamiya A, Shishido T, Tokudome T, Hosoda H, Shirai M, Kangawa K, Sugimachi M (2011) Centrally administered ghrelin activates cardiac vagal nerve in anesthetized rabbits. Auton Neurosci 162:60–65

    PubMed  CAS  Google Scholar 

  239. Serra-Prat M, Fernandez X, Burdoy E, Mussoll J, Casamitjana R, Puig-Domingo M (2007) The role of ghrelin in the energy homeostasis of elderly people: a population-based study. J Endocrinol Investig 30:484–490

    CAS  Google Scholar 

  240. Nass R, Farhy LS, Liu J, Pezzoli SS, Johnson ML, Gaylinn BD, Thorner MO (2014) Age-dependent decline in acyl-ghrelin concentrations and reduced association of acyl-ghrelin and growth hormone in healthy older adults. J Clin Endocrinol Metab 99:602–608

    PubMed  CAS  Google Scholar 

  241. Yin Y, Zhang W (2016) The role of ghrelin in senescence: a mini-review. Gerontology 62:155–162

    PubMed  CAS  Google Scholar 

  242. Kozakowski J, Rabijewski M, Zgliczynski W (2008) Ghrelin - growth hormone releasing and orexigenic hormone in men declines with age, insulin and with decrease in testosterone concentration. Neuro Endocrinol Lett 29(p):100–106

    PubMed  CAS  Google Scholar 

  243. Rigamonti AE, Pincelli AI, Corra B, Viarengo R, Bonomo SM, Galimberti D, Scacchi M, Scarpini E, Cavagnini F, Muller EE (2002) Plasma ghrelin concentrations in elderly subjects: comparison with anorexic and obese patients. J Endocrinol 175:1–5

    Google Scholar 

  244. Sturm K, MacIntosh CG, Parker BA, Wishart J, Horowitz M, Chapman IM (2003) Appetite, food intake, and plasma concentrations of cholecystokinin, ghrelin, and other gastrointestinal hormones in undernourished older women and well-nourished young and older women. J Clin Endocrinol Metab 88:3747–3755

    PubMed  CAS  Google Scholar 

  245. Yano Y, Nakazato M, Toshinai K, Inokuchi T, Matsuda S, Hidaka T, Hayakawa M, Kangawa K, Shimada K, Kario K (2014) Circulating des-acyl ghrelin improves cardiovascular risk prediction in older hypertensive patients. Am J Hypertens 27:727–733

    PubMed  CAS  Google Scholar 

  246. Liu YL, Yakar S, Otero-Corchon V, Low MJ, Liu JL (2002) Ghrelin gene expression is age-dependent and influenced by gender and the level of circulating IGF-I. Mol Cell Endocrinol 189:97–103

    PubMed  CAS  Google Scholar 

  247. Wolden-Hanson T (2006) Mechanisms of the anorexia of aging in the Brown Norway rat. Physiol Behav 88:267–276

    PubMed  CAS  Google Scholar 

  248. Kappeler L, Zizzari P, Alliot J, Epelbaum J, Bluet-Pajot MT (2004) Delayed age-associated decrease in growth hormone pulsatile secretion and increased orexigenic peptide expression in the Lou C/JaLL rat. Neuroendocrinology 80:273–283

    PubMed  CAS  Google Scholar 

  249. Akimoto Y, Kanai S, Ohta M, Akimoto S, Uematsu H, Miyasaka K (2012) Age-associated reduction of stimulatory effect of ghrelin on food intake in mice. Arch Gerontol Geriatr 55:238–243

    PubMed  CAS  Google Scholar 

  250. Sun Y, Garcia JM, Smith RG (2007) Ghrelin and growth hormone secretagogue receptor expression in mice during aging. Endocrinology 148:1323–1329

    PubMed  CAS  Google Scholar 

  251. Fujitsuka N, Asakawa A, Morinaga A, Amitani MS, Amitani H, Katsuura G, Sawada Y, Sudo Y, Uezono Y, Mochiki E, Sakata I, Sakai T, Hanazaki K, Yada T, Yakabi K, Sakuma E, Ueki T, Niijima A, Nakagawa K, Okubo N et al (2016) Increased ghrelin signaling prolongs survival in mouse models of human aging through activation of sirtuin1. Mol Psychiatry 21:1613–1623

    PubMed  PubMed Central  CAS  Google Scholar 

  252. North BJ, Sinclair DA (2012) The intersection between aging and cardiovascular disease. Circ Res 110:1097–1108

    PubMed  PubMed Central  CAS  Google Scholar 

  253. Sullivan R, Randhawa VK, Stokes A, Wu D, Lalonde T, Kiaii B, Luyt L, Wisenberg G, Dhanvantari S (2019) Dynamics of the ghrelin/growth hormone secretagogue receptor system in the human heart before and after cardiac transplantation. Journal of the Endocrine Society 3:748–762

    PubMed  PubMed Central  CAS  Google Scholar 

  254. Wren AM, Seal LJ, Cohen MA et al (2001) Ghrelin enhances appetite and increases food intake in humans. J Clin Endocrinol Metab 86:5992

    PubMed  CAS  Google Scholar 

  255. Trippel TD, Holzendorf V, Halle M, Gelbrich G, Nolte K, Duvinage A, Schwarz S, Rutscher T, Wiora J, Wachter R, Herrmann-Lingen C (2017) Ghrelin and hormonal markers under exercise training in patients with heart failure with preserved ejection fraction: results from the Ex-DHF pilot study. ESC Heart Failure 4:56–65

    PubMed  Google Scholar 

  256. Tesauro M, Schinzari F, Rovella V, Di Daniele N, Lauro D, Mores N, Veneziani A, Cardillo C (2009) Ghrelin restores the endothelin 1/nitric oxide balance in patients with obesity-related metabolic syndrome. Hypertension 54:995–1000

    PubMed  CAS  Google Scholar 

  257. Togliatto G, Trombetta A, Dentelli P, Baragli A, Rosso A, Granata R, Ghigo D, Pegoraro L, Ghigo E, Brizzi MF (2010) Unacylated ghrelin rescues endothelial progenitor cell function in individuals with type 2 diabetes. Diabetes 59:1016–1025

    PubMed  PubMed Central  CAS  Google Scholar 

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SG conceived the idea and prepared the manuscript as well as the figures. AM edited the draft manuscript and checked and arranged the references. Both the authors approved the final version of the manuscript.

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Gupta, S., Mitra, A. Heal the heart through gut (hormone) ghrelin: a potential player to combat heart failure. Heart Fail Rev 26, 417–435 (2021). https://doi.org/10.1007/s10741-020-10032-2

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