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Irisin Regulates Cardiac Responses to Exercise in Health and Diseases: a Narrative Review

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Abstract

Exercise has been recognized as an important non-pharmacological approach for the prevention, treatment, and rehabilitation of cardiovascular diseases, but the mechanisms of exercise in promoting cardiovascular health remain unclear. Exercise generates cardiac benefits via stimulating muscle to secret hundreds of myokines that directly enter circulation and target heart tissue. Therefore, inter-organ communication between skeletal muscle and heart may be one important regulating pattern, and such communication can occur through secretion of molecules, frequently known as myokines. Irisin, a newly identified myokine, is cleaved from fibronectin type III domain-containing protein 5 (FNDC5) and secreted by the stimulation of exercise. Recently, accumulating evidence focusing on the interaction between irisin and cardiac function has been reported. This review highlights the molecular signaling by which irisin regulates the benefits of exercise on cardiac function both in physiological and pathological process, and discusses the clinical potential of irisin in treating heart diseases.

Graphical abstract

Exercise generates various cardiovascular benefits through stimulating skeletal muscle to secrete irisin. The exercise “hormone” irisin, both produced by exercise or recombinant form, exerts therapeutic effects in a group of cardiovascular disorders including heart failure, myocardial infarction, atherosclerosis and hypertension. However, the molecular mechanisms involved remain ambiguous.This review highlights the most up-to-date findings to bridge the gap between exercise, irisin and cardiovascular diseases, and discusses the potential clinical prospect of irisin

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References

  1. Pinto FJ, Piñeiro D, Banerjee A, Perel P, Pervan B, Eiselé J-L. World Heart Day 2021: COVID-19, digital health, and tackling cardiovascular disease. Lancet. 2021;398(10310):1467–8. https://doi.org/10.1016/S0140-6736(21)02144-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Bloom D, Cafiero E, Jané-Llopis E, Abrahams-Gessel S, Bloom L, Fathima S, et al. The global economic burden of noncommunicable diseases. Geneva: World Economic Forum; 2011. https://www3.weforum.org/docs/WEF_Harvard_HE_GlobalEconomicBurdenNonCommunicableDiseases_2011.pdf. Accessed 21 May 2021.

  3. Yusuf S, Hawken S, Ôunpuu S, Dans T, Avezum A, Lanas F, et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet. 2004;364(9438):937–52. https://doi.org/10.1016/S0140-6736(04)17018-9.

    Article  PubMed  Google Scholar 

  4. Gelchu T, Abdela J. Drug therapy problems among patients with cardiovascular disease admitted to the medical ward and had a follow-up at the ambulatory clinic of Hiwot Fana Specialized University Hospital: the case of a tertiary hospital in eastern Ethiopia. SAGE Open Med. 2019;7:2050312119860401. https://doi.org/10.1177/2050312119860401.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Rubin DA, Nieminski KE, Monteferrante JC, Magee T, Reed GE, Herman MV. Ventricular arrhythmias after coronary artery bypass graft surgery: incidence, risk factors and long-term prognosis. J Am Coll Cardiol. 1985;6(2):307–10. https://doi.org/10.1016/S0735-1097(85)80165-0.

    Article  CAS  PubMed  Google Scholar 

  6. Timmis A, Townsend N, Gale CP, Torbica A, Lettino M, Petersen SE, et al. European Society of Cardiology: cardiovascular disease statistics 2019. Eur Heart J. 2020;41(1):12–85. https://doi.org/10.1093/eurheartj/ehz859.

    Article  PubMed  Google Scholar 

  7. Blair SN, Cheng Y, Holder JS. Is physical activity or physical fitness more important in defining health benefits? Med Sci Sports Exerc. 2001;33(6):S379–99. https://doi.org/10.1097/00005768-200106001-00007.

    Article  CAS  PubMed  Google Scholar 

  8. Dunn AL, Marcus BH, Kampert JB, Garcia ME, Kohl Iii HW, Blair SN. Comparison of lifestyle and structured interventions to increase physical activity and cardiorespiratory fitness: a randomized trial. JAMA. 1999;281(4):327–34.

    Article  CAS  PubMed  Google Scholar 

  9. Blair SN, Kampert JB, Kohl HW, Barlow CE, Macera CA, Paffenbarger RS, et al. Influences of cardiorespiratory fitness and other precursors on cardiovascular disease and all-cause mortality in men and women. JAMA. 1996;276(3):205–10.

    Article  CAS  PubMed  Google Scholar 

  10. Wen CP, Wai JPM, Tsai MK, Yang YC, Cheng TYD, Lee M-C, et al. Minimum amount of physical activity for reduced mortality and extended life expectancy: a prospective cohort study. Lancet. 2011;378(9798):1244–53. https://doi.org/10.1016/S0140-6736(11)60749-6.

    Article  PubMed  Google Scholar 

  11. Ferrer-Martínez A, Ruiz-Lozano P, Chien KR. Mouse PeP: a novel peroxisomal protein linked to myoblast differentiation and development. Dev Dyn. 2002;224(2):154–67. https://doi.org/10.1002/dvdy.10099.

    Article  CAS  PubMed  Google Scholar 

  12. Teufel A, Malik N, Mukhopadhyay M, Westphal H. Frcp1 and Frcp2, two novel fibronectin type III repeat containing genes. Gene. 2002;297(1–2):79–83. https://doi.org/10.1016/S0378-1119(02)00828-4.

    Article  CAS  PubMed  Google Scholar 

  13. Boström P, Wu J, Jedrychowski MP, Korde A, Ye L, Lo JC, et al. A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature. 2012;481(7382):463–8. https://doi.org/10.1038/nature10777.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Huh JY, Panagiotou G, Mougios V, Brinkoetter M, Vamvini MT, Schneider BE, et al. FNDC5 and irisin in humans: I. Predictors of circulating concentrations in serum and plasma and II. mRNA expression and circulating concentrations in response to weight loss and exercise. Metabolism. 2012;61(12):1725–38. https://doi.org/10.1016/j.metabol.2012.09.002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Huerta-Delgado AS, Roffe-Vazquez DN, Gonzalez-Gil AM, Villarreal-Calderón JR, Tamez-Rivera O, Rodriguez-Gutierrez NA, et al. Serum irisin levels, endothelial dysfunction, and inflammation in pediatric patients with type 2 diabetes mellitus and metabolic syndrome. J Diabetes Res. 2020;2020:1949415. https://doi.org/10.1155/2020/1949415.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Jedrychowski MP, Wrann CD, Paulo JA, Gerber KK, Szpyt J, Robinson MM, et al. Detection and quantitation of circulating human irisin by tandem mass spectrometry. Cell Metab. 2015;22(4):734–40. https://doi.org/10.1016/j.cmet.2015.08.001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Yin C, Hu W, Wang M, Lv W, Jia T, Xiao Y. Irisin as a mediator between obesity and vascular inflammation in Chinese children and adolescents. Nutr Metab Cardiovasc Dis. 2020;30(2):320–9. https://doi.org/10.1016/j.numecd.2019.09.025.

    Article  CAS  PubMed  Google Scholar 

  18. Norheim F, Langleite TM, Hjorth M, Holen T, Kielland A, Stadheim HK, et al. The effects of acute and chronic exercise on PGC-1α, irisin and browning of subcutaneous adipose tissue in humans. FEBS J. 2014;281(3):739–49. https://doi.org/10.1111/febs.12619.

    Article  CAS  PubMed  Google Scholar 

  19. Abedpoor N, Taghian F, Ghaedi K, Niktab I, Safaeinejad Z, Rabiee F, et al. PPARγ/Pgc-1α-Fndc5 pathway up-regulation in gastrocnemius and heart muscle of exercised, branched chain amino acid diet fed mice. Nutr Metab. 2018;15(1):59. https://doi.org/10.1186/s12986-018-0298-3.

    Article  CAS  Google Scholar 

  20. Tsuchiya Y, Ando D, Takamatsu K, Goto K. Resistance exercise induces a greater irisin response than endurance exercise. Metabolism. 2015;64(9):1042–50. https://doi.org/10.1016/j.metabol.2015.05.010.

    Article  CAS  PubMed  Google Scholar 

  21. Choi Y-K, Kim M-K, Bae KH, Seo H-A, Jeong J-Y, Lee W-K, et al. Serum irisin levels in new-onset type 2 diabetes. Diabetes Res Clin Pract. 2013;100(1):96–101. https://doi.org/10.1016/j.diabres.2013.01.007.

    Article  CAS  PubMed  Google Scholar 

  22. Yan B, Shi X, Zhang H, Pan L, Ma Z, Liu S, et al. Association of serum irisin with metabolic syndrome in obese Chinese adults. PLoS One. 2014;9(4):e94235. https://doi.org/10.1371/journal.pone.0094235.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Hou N, Han F, Sun X. The relationship between circulating irisin levels and endothelial function in lean and obese subjects. Clin Endocrinol. 2015;83(3):339–43. https://doi.org/10.1111/cen.12658.

    Article  CAS  Google Scholar 

  24. Deng J, Zhang N, Chen F, Yang C, Ning H, Xiao C, et al. Irisin ameliorates high glucose-induced cardiomyocytes injury via AMPK/mTOR signal pathway. Cell Biol Int. 2020;44(11):2315–25. https://doi.org/10.1002/cbin.11441.

    Article  CAS  PubMed  Google Scholar 

  25. Guo Q, Wei X, Hu H, Yang D, Zhang B, Fan X, et al. The saturated fatty acid palmitate induces insulin resistance through Smad3-mediated down-regulation of FNDC5 in myotubes. Biochem Biophys Res Commun. 2019;520(3):619–26. https://doi.org/10.1016/j.bbrc.2019.10.077.

    Article  CAS  PubMed  Google Scholar 

  26. Seo DY, Bae JH, Kim TN, Kwak H-B, Kha PT, Han J. Exercise-induced circulating irisin level is correlated with improved cardiac function in rats. Int J Environ Res Public Health. 2020;17(11). https://doi.org/10.3390/ijerph17113863.

  27. Patel CN. The signs and symptoms of coronary heart disease. East Afr Med J. 1963;40:319–21.

    CAS  PubMed  Google Scholar 

  28. Bösner S, Becker A, Hani MA, Keller H, Sönnichsen AC, Haasenritter J, et al. Accuracy of symptoms and signs for coronary heart disease assessed in primary care. Br J Gen Pract. 2010;60(575):e246. https://doi.org/10.3399/bjgp10X502137.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, et al. Heart disease and stroke statistics—2016 update. Circulation. 2016;133(4):e38–360. https://doi.org/10.1161/CIR.0000000000000350.

    Article  PubMed  Google Scholar 

  30. Vos T, Allen C, Arora M, Barber RM, Bhutta ZA, Brown A, et al. Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet. 2016;388(10053):1545–602. https://doi.org/10.1016/S0140-6736(16)31678-6.

    Article  Google Scholar 

  31. Authors/Task Force M, Steg PG, James SK, Atar D, Badano LP, Lundqvist CB, et al. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: the Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology (ESC). Eur Heart J. 2012;33(20):2569–619. https://doi.org/10.1093/eurheartj/ehs215.

    Article  CAS  Google Scholar 

  32. Murray CJL, Barber RM, Foreman KJ, Ozgoren AA, Abd-Allah F, Abera SF, et al. Global, regional, and national disability-adjusted life years (DALYs) for 306 diseases and injuries and healthy life expectancy (HALE) for 188 countries, 1990–2013: quantifying the epidemiological transition. Lancet. 2015;386(10009):2145–91. https://doi.org/10.1016/S0140-6736(15)61340-X.

    Article  PubMed  Google Scholar 

  33. Dun SL, Lyu RM, Chen YH, Chang JK, Luo JJ, Dun NJ. Irisin-immunoreactivity in neural and non-neural cells of the rodent. Neuroscience. 2013;240:155–62. https://doi.org/10.1016/j.neuroscience.2013.02.050.

    Article  CAS  PubMed  Google Scholar 

  34. Gür FM, Timurkaan S, Yalcin MH, Girgin A, Gençer TB. Immunohistochemical localization of irisin in mole rats (Spalax leucodon). Biotech Histochem. 2017;92(4):245–51. https://doi.org/10.1080/10520295.2017.1303194.

    Article  CAS  PubMed  Google Scholar 

  35. Sundarrajan L, Yeung C, Hahn L, Weber LP, Unniappan S. Irisin regulates cardiac physiology in zebrafish. PLoS One. 2017;12(8):e0181461. https://doi.org/10.1371/journal.pone.0181461.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Zhao YT, Wang J, Yano N, Zhang LX, Wang H, Zhang S, et al. Irisin promotes cardiac progenitor cell-induced myocardial repair and functional improvement in infarcted heart. J Cell Physiol. 2019;234(2):1671–81. https://doi.org/10.1002/jcp.27037.

    Article  CAS  PubMed  Google Scholar 

  37. Emanuele E, Minoretti P, Pareja-Galeano H, Sanchis-Gomar F, Garatachea N, Lucia A. Serum irisin levels, precocious myocardial infarction, and healthy exceptional longevity. Am J Med. 2014;127(9):888–90. https://doi.org/10.1016/j.amjmed.2014.04.025.

    Article  CAS  PubMed  Google Scholar 

  38. Anastasilakis AD, Koulaxis D, Kefala N, Polyzos SA, Upadhyay J, Pagkalidou E, et al. Circulating irisin levels are lower in patients with either stable coronary artery disease (CAD) or myocardial infarction (MI) versus healthy controls, whereas follistatin and activin A levels are higher and can discriminate MI from CAD with similar to CK-MB accuracy. Metabolism. 2017;73:1–8. https://doi.org/10.1016/j.metabol.2017.05.002.

    Article  CAS  PubMed  Google Scholar 

  39. Zuurbier CJ, Bertrand L, Beauloye CR, Andreadou I, Ruiz-Meana M, Jespersen NR, et al. Cardiac metabolism as a driver and therapeutic target of myocardial infarction. J Cell Mol Med. 2020;24(11):5937–54. https://doi.org/10.1111/jcmm.15180.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Xin T, Lu C. Irisin activates Opa1-induced mitophagy to protect cardiomyocytes against apoptosis following myocardial infarction. Aging. 2020;12(5):4474–88. https://doi.org/10.18632/aging.102899.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Liao Q, Qu S, Tang L-x, Li L-p, He D-f, Zeng C-y, et al. Irisin exerts a therapeutic effect against myocardial infarction via promoting angiogenesis. Acta Pharmacol Sin. 2019;40(10):1314–21. https://doi.org/10.1038/s41401-019-0230-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Zhao YT, Wang H, Zhang S, Du J, Zhuang S, Zhao TC. Irisin ameliorates hypoxia/reoxygenation-induced injury through modulation of histone deacetylase 4. PLoS ONE. 2016;11(11):e0166182. https://doi.org/10.1371/journal.pone.0166182.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Lenaz G. Role of mitochondria in oxidative stress and ageing. Biochim Biophys Acta. 1998;1366(1):53–67. https://doi.org/10.1016/S0005-2728(98)00120-0.

    Article  CAS  PubMed  Google Scholar 

  44. Rigoulet M, Yoboue ED, Devin A. Mitochondrial ROS generation and its regulation: mechanisms involved in H2O2 signaling. Antioxid Redox Signal. 2010;14(3):459–68. https://doi.org/10.1089/ars.2010.3363.

    Article  CAS  PubMed  Google Scholar 

  45. Li H, Qin S, Liang Q, Xi Y, Bo W, Cai M, et al. Exercise training enhances myocardial mitophagy and improves cardiac function via irisin/FNDC5-PINK1/parkin pathway in MI mice. Biomedicines. 2021;9(6). https://doi.org/10.3390/biomedicines9060701.

  46. Chen Y-R, Chen C-L, Pfeiffer DR, Zweier JL. Mitochondrial complex II in the post-ischemic heart: oxidative injury and the role of protein S-glutathionylation. J Biol Chem. 2007;282(45):32640–54. https://doi.org/10.1074/jbc.M702294200.

    Article  CAS  PubMed  Google Scholar 

  47. Davidson SM, Adameová A, Barile L, Cabrera-Fuentes HA, Lazou A, Pagliaro P, et al. Mitochondrial and mitochondrial-independent pathways of myocardial cell death during ischaemia and reperfusion injury. J Cell Mol Med. 2020;24(7):3795–806. https://doi.org/10.1111/jcmm.15127.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Kubli DA, Gustafsson ÅB. Mitochondria and mitophagy. Circ Res. 2012;111(9):1208–21. https://doi.org/10.1161/CIRCRESAHA.112.265819.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Baechler BL, Bloemberg D, Quadrilatero J. Mitophagy regulates mitochondrial network signaling, oxidative stress, and apoptosis during myoblast differentiation. Autophagy. 2019;15(9):1606–19. https://doi.org/10.1080/15548627.2019.1591672.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Hall AR, Burke N, Dongworth RK, Hausenloy DJ. Mitochondrial fusion and fission proteins: novel therapeutic targets for combating cardiovascular disease. Br J Pharmacol. 2014;171(8):1890–906. https://doi.org/10.1111/bph.12516.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Vásquez-Trincado C, García-Carvajal I, Pennanen C, Parra V, Hill JA, Rothermel BA, et al. Mitochondrial dynamics, mitophagy and cardiovascular disease. J Physiol. 2016;594(3):509–25. https://doi.org/10.1113/JP271301.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Narendra D, Tanaka A, Suen D-F, Youle RJ. Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J Cell Biol. 2008;183(5):795–803. https://doi.org/10.1083/jcb.200809125.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Komatsu M, Ichimura Y. Physiological significance of selective degradation of p62 by autophagy. FEBS Lett. 2010;584(7):1374–8. https://doi.org/10.1016/j.febslet.2010.02.017.

    Article  CAS  PubMed  Google Scholar 

  54. Tanida I, Ueno T, Kominami E. LC3 and autophagy. In: Deretic V, editor. Methods in molecular biology. Totowa: Humana Press; 2008. pp. 77–88.

    Google Scholar 

  55. Lu L, Ma J, Tang J, Liu Y, Zheng Q, Chen S, et al. Irisin attenuates myocardial ischemia/reperfusion-induced cardiac dysfunction by regulating ER-mitochondria interaction through a mitochondrial ubiquitin ligase-dependent mechanism. Clin Transl Med. 2020;10(5):e166. https://doi.org/10.1002/ctm2.166.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Metra M, Teerlink JR. Heart failure. Lancet. 2017;390(10106):1981–95. https://doi.org/10.1016/S0140-6736(17)31071-1.

    Article  PubMed  Google Scholar 

  57. Li R-L, Wu S-S, Wu Y, Wang X-X, Chen H-Y, Xin J-j, et al. Irisin alleviates pressure overload-induced cardiac hypertrophy by inducing protective autophagy via mTOR-independent activation of the AMPK-ULK1 pathway. J Mol Cell Cardiol. 2018;121:242–55. https://doi.org/10.1016/j.yjmcc.2018.07.250.

    Article  CAS  PubMed  Google Scholar 

  58. Yu Q, Kou W, Xu X, Zhou S, Luan P, Xu X, et al. FNDC5/irisin inhibits pathological cardiac hypertrophy. Clin Sci. 2019;133(5):611–27. https://doi.org/10.1042/CS20190016.

    Article  CAS  Google Scholar 

  59. Chen R-R, Fan X-H, Chen G, Zeng G-W, Xue Y-G, Liu X-T, et al. Irisin attenuates angiotensin II-induced cardiac fibrosis via Nrf2 mediated inhibition of ROS/TGFβ1/Smad2/3 signaling axis. Chem Biol Interact. 2019;302:11–21. https://doi.org/10.1016/j.cbi.2019.01.031.

    Article  CAS  PubMed  Google Scholar 

  60. Tsutsui H, Kinugawa S, Matsushima S. Oxidative stress and heart failure. Am J Physiol Heart Circ Physiol. 2011;301(6):H2181–90. https://doi.org/10.1152/ajpheart.00554.2011.

    Article  CAS  PubMed  Google Scholar 

  61. Zhao W, Zhao T, Chen Y, Ahokas RA, Sun Y. Oxidative stress mediates cardiac fibrosis by enhancing transforming growth factor-beta1 in hypertensive rats. Mol Cell Biochem. 2008;317(1):43–50. https://doi.org/10.1007/s11010-008-9803-8.

    Article  CAS  PubMed  Google Scholar 

  62. Siwik DA, Pagano PJ, Colucci WS. Oxidative stress regulates collagen synthesis and matrix metalloproteinase activity in cardiac fibroblasts. Am J Physiol Cell Physiol. 2001;280(1):C53–60. https://doi.org/10.1152/ajpcell.2001.280.1.C53.

    Article  CAS  PubMed  Google Scholar 

  63. Nakai A, Yamaguchi O, Takeda T, Higuchi Y, Hikoso S, Taniike M, et al. The role of autophagy in cardiomyocytes in the basal state and in response to hemodynamic stress. Nat Med. 2007;13(5):619–24. https://doi.org/10.1038/nm1574.

    Article  CAS  PubMed  Google Scholar 

  64. Daskalopoulos EP, Dufeys C, Bertrand L, Beauloye C, Horman S. AMPK in cardiac fibrosis and repair: actions beyond metabolic regulation. J Mol Cell Cardiol. 2016;91:188–200. https://doi.org/10.1016/j.yjmcc.2016.01.001.

    Article  CAS  PubMed  Google Scholar 

  65. Horman S, Beauloye C, Vanoverschelde J-L, Bertrand L. AMP-activated protein kinase in the control of cardiac metabolism and remodeling. Curr Heart Fail Rep. 2012;9(3):164–73. https://doi.org/10.1007/s11897-012-0102-z.

    Article  CAS  PubMed  Google Scholar 

  66. Sciarretta S, Forte M, Frati G, Sadoshima J. New insights into the role of mTOR signaling in the cardiovascular system. Circ Res. 2018;122(3):489–505. https://doi.org/10.1161/CIRCRESAHA.117.311147.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Aronow WS, Fleg JL, Rich MW. Tresch and Aronow’s cardiovascular disease in the elderly. 6th ed. Boca Raton: CRC Press; 2019.

    Book  Google Scholar 

  68. Sarwar N, Danesh J, Eiriksdottir G, Sigurdsson G, Wareham N, Bingham S, et al. Triglycerides and the risk of coronary heart disease. Circulation. 2007;115(4):450–8. https://doi.org/10.1161/CIRCULATIONAHA.106.637793.

    Article  CAS  PubMed  Google Scholar 

  69. The Emerging Risk Factors C. Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA. 2009;302(4):412–23. https://doi.org/10.1001/jama.2009.1063.

    Article  Google Scholar 

  70. Davies MJ, Gordon JL, Gearing AJH, Pigott R, Woolf N, Katz D, et al. The expression of the adhesion molecules ICAM-1, VCAM-1, PECAM, and E-selectin in human atherosclerosis. J Pathol. 1993;171(3):223–9. https://doi.org/10.1002/path.1711710311.

    Article  CAS  PubMed  Google Scholar 

  71. O’Brien KD, Allen MD, McDonald TO, Chait A, Harlan JM, Fishbein D, et al. Vascular cell adhesion molecule-1 is expressed in human coronary atherosclerotic plaques. Implications for the mode of progression of advanced coronary atherosclerosis. J Clin Investig. 1993;92(2):945–51.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Johnson-Tidey RR, McGregor JL, Taylor PR, Poston RN. Increase in the adhesion molecule P-selectin in endothelium overlying atherosclerotic plaques Coexpression with intercellular adhesion molecule-1. Am J Pathol. 1994;144(5):952.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Zhang Y, Mu Q, Zhou Z, Song H, Zhang Y, Wu F, et al. Protective effect of irisin on atherosclerosis via suppressing oxidized low density lipoprotein induced vascular inflammation and endothelial dysfunction. PLoS One. 2016;11(6):e0158038. https://doi.org/10.1371/journal.pone.0158038.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Lu J, Xiang G, Liu M, Mei W, Xiang L, Dong J. Irisin protects against endothelial injury and ameliorates atherosclerosis in apolipoprotein E-Null diabetic mice. Atherosclerosis. 2015;243(2):438–48. https://doi.org/10.1016/j.atherosclerosis.2015.10.020.

    Article  CAS  PubMed  Google Scholar 

  75. Zhang Y, Song H, Zhang Y, Wu F, Mu Q, Jiang M, et al. Irisin inhibits atherosclerosis by promoting endothelial proliferation through microRNA126-5p. J Am Heart Assoc. 2016;5(9):e004031. https://doi.org/10.1161/JAHA.116.004031.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Stanaway JD, Afshin A, Gakidou E, Lim SS, Abate D, Abate KH, et al. Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392(10159):1923–94. https://doi.org/10.1016/S0140-6736(18)32225-6.

    Article  Google Scholar 

  77. Versari D, Daghini E, Virdis A, Ghiadoni L, Taddei S. Endothelium-dependent contractions and endothelial dysfunction in human hypertension. Br J Pharmacol. 2009;157(4):527–36. https://doi.org/10.1111/j.1476-5381.2009.00240.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Marchesi C, Paradis P, Schiffrin EL. Role of the renin-angiotensin system in vascular inflammation. Trends Pharmacol Sci. 2008;29(7):367–74. https://doi.org/10.1016/j.tips.2008.05.003.

    Article  CAS  PubMed  Google Scholar 

  79. Hermann M, Flammer A, Lüscher TF. Nitric oxide in hypertension. J Clin Hypertens. 2006;8(s12):17–29. https://doi.org/10.1111/j.1524-6175.2006.06032.x.

    Article  CAS  Google Scholar 

  80. Panza JA. Endothelial dysfunction in essential hypertension. Clin Cardiol. 1997;20(S2):II26–33. https://doi.org/10.1002/j.1932-8737.1997.tb00009.x.

    Article  Google Scholar 

  81. Inoue K, Fujie S, Hasegawa N, Horii N, Uchida M, Iemitsu K, et al. Aerobic exercise training-induced irisin secretion is associated with the reduction of arterial stiffness via nitric oxide production in adults with obesity. Appl Physiol Nutr Metab. 2019;45(7):715–22. https://doi.org/10.1139/apnm-2019-0602.

    Article  CAS  PubMed  Google Scholar 

  82. Fu J, Han Y, Wang J, Liu Y, Zheng S, Zhou L, et al. Irisin lowers blood pressure by improvement of endothelial dysfunction via AMPK-Akt-eNOS-NO pathway in the spontaneously hypertensive rat. J Am Heart Assoc. 2016;5(11):e003433. https://doi.org/10.1161/JAHA.116.003433.

    Article  PubMed  PubMed Central  Google Scholar 

  83. Liu C, Ngai C-Y, Huang Y, Ko W-H, Wu M, He G-W, et al. Depletion of intracellular Ca2+ stores enhances flow-induced vascular dilatation in rat small mesenteric artery. Br J Pharmacol. 2006;147(5):506–15. https://doi.org/10.1038/sj.bjp.0706639.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Goldsmith DJA, Covic AA, Venning MC, Ackrill P. Blood pressure reduction after parathyroidectomy for secondary hyperparathyroidism: further evidence implicating calcium homeostasis in blood pressure regulation. Am J Kidney Dis. 1996;27(6):819–25. https://doi.org/10.1016/S0272-6386(96)90519-3.

    Article  CAS  PubMed  Google Scholar 

  85. Du J, Wang X, Li J, Guo J, Liu L, Yan D, et al. Increasing TRPV4 expression restores flow-induced dilation impaired in mesenteric arteries with aging. Sci Rep. 2016;6(1):22780. https://doi.org/10.1038/srep22780.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Zhang P, Sun C, Li H, Tang C, Kan H, Yang Z, et al. TRPV4 (transient receptor potential vanilloid 4) mediates endothelium-dependent contractions in the aortas of hypertensive mice. Hypertension. 2018;71(1):134–42. https://doi.org/10.1161/HYPERTENSIONAHA.117.09767.

    Article  CAS  PubMed  Google Scholar 

  87. Ye L, Xu M, Hu M, Zhang H, Tan X, Li Q, et al. TRPV4 is involved in irisin-induced endothelium-dependent vasodilation. Biochem Biophys Res Commun. 2018;495(1):41–5. https://doi.org/10.1016/j.bbrc.2017.10.160.

    Article  CAS  PubMed  Google Scholar 

  88. Zhang W, Chang L, Zhang C, Zhang R, Li Z, Chai B, et al. Central and peripheral irisin differentially regulate blood pressure. Cardiovasc Drugs Ther. 2015;29(2):121–7. https://doi.org/10.1007/s10557-015-6580-y.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Touyz RM, Alves-Lopes R, Rios FJ, Camargo LL, Anagnostopoulou A, Arner A, et al. Vascular smooth muscle contraction in hypertension. Cardiovasc Res. 2018;114(4):529–39. https://doi.org/10.1093/cvr/cvy023.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Tostes RCA, Wilde DW, Bendhack LM, Webb RC. Calcium handling by vascular myocytes in hypertension. Braz J Med Biol Res. 1997;30:315–23.

    Article  CAS  PubMed  Google Scholar 

  91. Jiang M, Wan F, Wang F, Wu Q. Irisin relaxes mouse mesenteric arteries through endothelium-dependent and endothelium-independent mechanisms. Biochem Biophys Res Commun. 2015;468(4):832–6. https://doi.org/10.1016/j.bbrc.2015.11.040.

    Article  CAS  PubMed  Google Scholar 

  92. Lambert E, Sari CI, Dawood T, Nguyen J, McGrane M, Eikelis N, et al. Sympathetic nervous system activity is associated with obesity-induced subclinical organ damage in young adults. Hypertension. 2010;56(3):351–8. https://doi.org/10.1161/HYPERTENSIONAHA.110.155663.

    Article  CAS  PubMed  Google Scholar 

  93. Harris KF, Matthews KA. Interactions between autonomic nervous system activity and endothelial function: a model for the development of cardiovascular disease. Psychosom Med. 2004;66(2):153–64. https://doi.org/10.1097/01.psy.0000116719.95524.e2.

    Article  PubMed  Google Scholar 

  94. Grassi G. Sympathetic neural activity in hypertension and related diseases. Am J Hypertens. 2010;23(10):1052–60. https://doi.org/10.1038/ajh.2010.154.

    Article  PubMed  Google Scholar 

  95. Martin DS, Haywood JR. Sympathetic nervous system activation by glutamate injections into the paraventricular nucleus. Brain Res. 1992;577(2):261–7. https://doi.org/10.1016/0006-8993(92)90282-E.

    Article  CAS  PubMed  Google Scholar 

  96. Coote JH, Yang Z, Pyner S, Deering J. Control of sympathetic outflows by the hypothalamic paraventricular nucleus. Clin Exp Pharmacol Physiol. 1998;25(6):461–3. https://doi.org/10.1111/j.1440-1681.1998.tb02235.x.

    Article  CAS  PubMed  Google Scholar 

  97. Kang Y-M, He R-L, Yang L-M, Qin D-N, Guggilam A, Elks C, et al. Brain tumour necrosis factor-α modulates neurotransmitters in hypothalamic paraventricular nucleus in heart failure. Cardiovasc Res. 2009;83(4):737–46. https://doi.org/10.1093/cvr/cvp160.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Qi J, Zhang D-M, Suo Y-P, Song X-A, Yu X-J, Elks C, et al. Renin–angiotensin system modulates neurotransmitters in the paraventricular nucleus and contributes to angiotensin II-induced hypertensive response. Cardiovasc Toxicol. 2013;13(1):48–54. https://doi.org/10.1007/s12012-012-9184-9.

    Article  CAS  PubMed  Google Scholar 

  99. Huo C-J, Yu X-J, Sun Y-J, Li H-B, Su Q, Bai J, et al. Irisin lowers blood pressure by activating the Nrf2 signaling pathway in the hypothalamic paraventricular nucleus of spontaneously hypertensive rats. Toxicol Appl Pharmacol. 2020;394:114953. https://doi.org/10.1016/j.taap.2020.114953.

    Article  CAS  PubMed  Google Scholar 

  100. Murry Charles E, Reinecke H, Pabon LM. Regeneration gaps. J Am Coll Cardiol. 2006;47(9):1777–85. https://doi.org/10.1016/j.jacc.2006.02.002.

    Article  CAS  PubMed  Google Scholar 

  101. Olivetti G, Melissari M, Capasso JM, Anversa P. Cardiomyopathy of the aging human heart. Myocyte loss and reactive cellular hypertrophy. Circ Res. 1991;68(6):1560–8. https://doi.org/10.1161/01.RES.68.6.1560.

    Article  CAS  PubMed  Google Scholar 

  102. Whelan RS, Kaplinskiy V, Kitsis RN. Cell death in the pathogenesis of heart disease: mechanisms and significance. Annu Rev Physiol. 2010;72(1):19–44. https://doi.org/10.1146/annurev.physiol.010908.163111.

    Article  CAS  PubMed  Google Scholar 

  103. Poss KD, Wilson LG, Keating MT. Heart regeneration in zebrafish. Science. 2002;298(5601):2188. https://doi.org/10.1126/science.1077857.

    Article  CAS  PubMed  Google Scholar 

  104. Laflamme MA, Murry CE. Heart regeneration. Nature. 2011;473(7347):326–35. https://doi.org/10.1038/nature10147.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Xie C, Zhang Y, Tran TDN, Wang H, Li S, George EV, et al. Irisin controls growth, intracellular Ca2+ signals, and mitochondrial thermogenesis in cardiomyoblasts. PLoS One. 2015;10(8):e0136816. https://doi.org/10.1371/journal.pone.0136816.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Deng J, Zhang N, Wang Y, Yang C, Wang Y, Xin C, et al. FNDC5/irisin improves the therapeutic efficacy of bone marrow-derived mesenchymal stem cells for myocardial infarction. Stem Cell Res Ther. 2020;11(1):228. https://doi.org/10.1186/s13287-020-01746-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Cao H, Kang BJ, Lee CA, Shung KK, Hsiai TK. Electrical and mechanical strategies to enable cardiac repair and regeneration. IEEE Rev Biomed Eng. 2015;8:114–24. https://doi.org/10.1109/RBME.2015.2431681.

    Article  PubMed  PubMed Central  Google Scholar 

  108. Hassaan PS, Nassar SZ, Issa Y, Zahran N. Irisin vs. treadmill exercise in post myocardial infarction cardiac rehabilitation in rats. Arch Med Res. 2019;50(2):44–54. https://doi.org/10.1016/j.arcmed.2019.05.009.

    Article  CAS  PubMed  Google Scholar 

  109. Bashar SM, Samir El-sherbeiny SM, Boraie MZ. Correlation between the blood level of irisin and the severity of acute myocardial infarction in exercise-trained rats. J Basic Clin Physiol Pharmacol. 2019;30(1):59–71. https://doi.org/10.1515/jbcpp-2018-0090.

    Article  CAS  Google Scholar 

  110. Han F, Zhang S, Hou N, Wang D, Sun X. Irisin improves endothelial function in obese mice through the AMPK-eNOS pathway. Am J Physiol Heart Circ Physiol. 2015;309(9):H1501–8. https://doi.org/10.1152/ajpheart.00443.2015.

    Article  CAS  PubMed  Google Scholar 

  111. Barrett-Connor E. Diabetes and heart disease. Diabetes Care. 2003;26(10):2947–58. https://doi.org/10.2337/diacare.26.10.2947.

    Article  PubMed  Google Scholar 

  112. Wright N, Wilson L, Smith M, Duncan B, McHugh P. The BROAD study: a randomised controlled trial using a whole food plant-based diet in the community for obesity, ischaemic heart disease or diabetes. Nutr Diabetes. 2017;7(3):e256. https://doi.org/10.1038/nutd.2017.3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Shirai K. Obesity as the core of the metabolic syndrome and the management of coronary heart disease. Curr Med Res Opin. 2004;20(3):295–304. https://doi.org/10.1185/030079903125003008.

    Article  PubMed  Google Scholar 

  114. Lopez-Legarrea P, de la Iglesia R, Crujeiras AB, Pardo M, Casanueva FF, Zulet MA, et al. Higher baseline irisin concentrations are associated with greater reductions in glycemia and insulinemia after weight loss in obese subjects. Nutr Diabetes. 2014;4(2):e110. https://doi.org/10.1038/nutd.2014.7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Lin C, Guo Y, Xia Y, Li C, Xu X, Qi T, et al. FNDC5/irisin attenuates diabetic cardiomyopathy in a type 2 diabetes mouse model by activation of integrin αV/β5-AKT signaling and reduction of oxidative/nitrosative stress. J Mol Cell Cardiol. 2021;160:27–41. https://doi.org/10.1016/j.yjmcc.2021.06.013.

    Article  CAS  PubMed  Google Scholar 

  116. Kattoor AJ, Pothineni NVK, Palagiri D, Mehta JL. Oxidative stress in atherosclerosis. Curr Atheroscler Rep. 2017;19(11):42. https://doi.org/10.1007/s11883-017-0678-6.

    Article  CAS  PubMed  Google Scholar 

  117. Wang Z, Chen K, Han Y, Zhu H, Zhou X, Tan T, et al. Irisin protects heart against ischemia-reperfusion injury through a SOD2-dependent mitochondria mechanism. J Cardiovasc Pharmacol. 2018;72(6):259–69. https://doi.org/10.1097/FJC.0000000000000608.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Wu F, Li Z, Cai M, Xi Y, Xu Z, Zhang Z, et al. Aerobic exercise alleviates oxidative stress-induced apoptosis in kidneys of myocardial infarction mice by inhibiting ALCAT1 and activating FNDC5/irisin signaling pathway. Free Radic Biol Med. 2020;158:171–80. https://doi.org/10.1016/j.freeradbiomed.2020.06.038.

    Article  CAS  PubMed  Google Scholar 

  119. Mazur-Bialy AI, Kozlowska K, Pochec E, Bilski J, Brzozowski T. Myokine irisin-induced protection against oxidative stress in vitro. Involvement of heme oxygenase-1 and antioxidazing enzymes superoxide dismutase-2 and glutathione peroxidase. J Physiol Pharmacol. 2018;69(1):117–25. https://doi.org/10.26402/jpp.2018.1.13.

    Article  CAS  PubMed  Google Scholar 

  120. Tsuchiya Y, Ando D, Goto K, Kiuchi M, Yamakita M, Koyama K. High-intensity exercise causes greater irisin response compared with low-intensity exercise under similar energy consumption. Tohoku J Exp Med. 2014;233(2):135–40. https://doi.org/10.1620/tjem.233.135.

    Article  PubMed  Google Scholar 

  121. Jandova T, Buendía-Romero A, Polanska H, Hola V, Rihova M, Vetrovsky T, et al. Long-term effect of exercise on irisin blood levels—systematic review and meta-analysis. Healthcare. 2021;9(11). https://doi.org/10.3390/healthcare9111438.

  122. Huang J, Wang S, Xu F, Wang D, Yin H, Lai Q, et al. Exercise training with dietary restriction enhances circulating irisin level associated with increasing endothelial progenitor cell number in obese adults: an intervention study. PeerJ. 2017;5:e3669. https://doi.org/10.7717/peerj.3669.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Conner EM, Grisham MB. Inflammation, free radicals, and antioxidants. Nutrition. 1996;12(4):274–7. https://doi.org/10.1016/S0899-9007(96)00000-8.

    Article  CAS  PubMed  Google Scholar 

  124. Brasier AR. The nuclear factor-κB–interleukin-6 signalling pathway mediating vascular inflammation. Cardiovasc Res. 2010;86(2):211–8. https://doi.org/10.1093/cvr/cvq076.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Deng X, Huang W, Peng J, Zhu T-T, Sun X-L, Zhou X-Y, et al. Irisin alleviates advanced glycation end products-induced inflammation and endothelial dysfunction via inhibiting ROS-NLRP3 inflammasome signaling. Inflammation. 2018;41(1):260–75. https://doi.org/10.1007/s10753-017-0685-3.

    Article  CAS  PubMed  Google Scholar 

  126. Erickson HP. Irisin and FNDC5 in retrospect. Adipocyte. 2013;2(4):289–93. https://doi.org/10.4161/adip.26082.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Kim H, Wrann CD, Jedrychowski M, Vidoni S, Kitase Y, Nagano K, et al. Irisin mediates effects on bone and fat via αV integrin receptors. Cell. 2018;175(7):1756-68.e17. https://doi.org/10.1016/j.cell.2018.10.025.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Funding

This study was funded in part by the Natural Science Foundation of Jiangsu Province (BK20201435).

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Authors and Affiliations

  1. College of Physical Education, Yangzhou University, 88 South Daxue Road, Yangzhou, 225009, Jiangsu, China

    Baishu Zhu, Bin Wang, Chen Zhao, Yuanxin Wang, Yalan Zhou, Junjie Lin & Renqing Zhao

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  1. Baishu Zhu
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  2. Bin Wang
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  3. Chen Zhao
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  4. Yuanxin Wang
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  5. Yalan Zhou
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  6. Junjie Lin
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  7. Renqing Zhao
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Contributions

All authors agreed to the study conception. Material preparation, data collection, and analysis were performed by Bin Wang, Chen Zhao, and Yuanxin Wang. The first draft of the manuscript was written by Baishu Zhu and revised by Yalan Zhou, Junjie Lin, and Renqing Zhao. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Renqing Zhao.

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Associate Editor Junjie Xiao oversaw the review of this article

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Zhu, B., Wang, B., Zhao, C. et al. Irisin Regulates Cardiac Responses to Exercise in Health and Diseases: a Narrative Review. J. of Cardiovasc. Trans. Res. 16, 430–442 (2023). https://doi.org/10.1007/s12265-022-10310-4

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