Skip to main content

Advertisement

Log in

Role of PI3K/Akt signaling pathway in cardiac fibrosis

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Heart failure (HF) is considered as a severe health problem worldwide, while cardiac fibrosis is one of the main driving factors for the progress of HF. Cardiac fibrosis was characterized by changes in cardiomyocytes, cardiac fibroblasts, ratio of collagen (COL) I/III, and the excessive production and deposition of extracellular matrix (ECM), thus forming a scar tissue, which leads to pathological process of cardiac structural changes and systolic as well as diastolic dysfunction. Cardiac fibrosis is a common pathological change of many advanced cardiovascular diseases including ischemic heart disease, hypertension, and HF. Accumulated studies have proven that phosphoinositol-3 kinase (PI3K)/Akt signaling pathway is involved in regulating the occurrence, progression and pathological formation of cardiac fibrosis via regulating cell survival, apoptosis, growth, cardiac contractility and even the transcription of related genes through a series of molecules including mammalian target of rapamycin (mTOR), glycogen synthase kinase 3 (GSK-3), forkhead box proteins O1/3 (FoxO1/3), and nitric oxide synthase (NOS). Thus, the review focuses on the role of PI3K/Akt signaling pathway in the cardiac fibrosis. The information reviewed here should be significant in understanding the role of PI3K/Akt in cardiac fibrosis and contribute to the design of further studies related to PI3K/Akt and the cardiac fibrotic response, as well as sought to shed light on a potential treatment for cardiac fibrosis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

We’re sorry, something doesn't seem to be working properly.

Please try refreshing the page. If that doesn't work, please contact support so we can address the problem.

Fig. 1
Fig. 2

Similar content being viewed by others

Data availability

Authors can confirm that all relevant data are included in the article or its supplementary information files.

References

  1. Schirone L, Forte M, Palmerio S, Yee D et al (2017) A review of the molecular mechanisms underlying the development and progression of cardiac remodeling. Oxid Med Cell Longev 2017:3920195

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Weeks KL, Bernardo BC, Ooi JYY et al (2017) The IGF1-PI3K-Akt signaling pathway in mediating exercise-induced cardiac hypertrophy and protection. Adv Exp Med Biol 1000:187–210

    Article  CAS  PubMed  Google Scholar 

  3. Xin Z, Ma Z, Hu W et al (2018) FOXO1/3: potential suppressors of fibrosis. Ageing Res Rev 41:42–52

    Article  CAS  PubMed  Google Scholar 

  4. Ma ZG, Yuan YP, Wu HM et al (2018) Cardiac fibrosis: new insights into the pathogenesis. Int J Biol Sci 14(12):1645–1657

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Talman V, Ruskoaho H (2016) Cardiac fibrosis in myocardial infarction-from repair and remodeling to regeneration. Cell Tissue Res 365(3):563–581

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Li YQ, Li XB, Guo SJ et al (2013) Apocynin attenuates oxidative stress and cardiac fibrosis in angiotensin II-induced cardiac diastolic dysfunction in mice. Acta Pharmacol Sin 34(3):352–359

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Kong P, Christia P, Frangogiannis NG (2014) The pathogenesis of cardiac fibrosis. Cell Mol Life Sci 71(4):549–574

    Article  CAS  PubMed  Google Scholar 

  8. Ponikowski P, Voors AA, Anker SD et al (2016) 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Rev Esp Cardiol (Engl Ed) 69(12):1167

    Google Scholar 

  9. Vedin O, Lam CSP, Koh AS et al (2017) Significance of ischemic heart disease in patients with heart failure and preserved, midrange, and reduced ejection fraction: a nationwide cohort study. Circ Heart Fail. https://doi.org/10.1161/CIRCHEARTFAILURE.117.003875

    Article  PubMed  Google Scholar 

  10. Bielecka-Dabrowa A, Sakowicz A, Misztal M et al (2016) Differences in biochemical and genetic biomarkers in patients with heart failure of various etiologies. Int J Cardiol 221:1073–1080

    Article  PubMed  Google Scholar 

  11. Cheng JM, Akkerhuis KM, Battes LC et al (2013) Biomarkers of heart failure with normal ejection fraction: a systematic review. Eur J Heart Fail 15(12):1350–1362

    Article  CAS  PubMed  Google Scholar 

  12. Martos R, Baugh J, Ledwidge M et al (2009) Diagnosis of heart failure with preserved ejection fraction: improved accuracy with the use of markers of collagen turnover. Eur J Heart Fail 11(2):191–197

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Roy C, Slimani A, de Meester C et al (2018) Associations and prognostic significance of diffuse myocardial fibrosis by cardiovascular magnetic resonance in heart failure with preserved ejection fraction. J Cardiovasc Magn Reson 20(1):55

    Article  PubMed  PubMed Central  Google Scholar 

  14. Kasner M, Westermann D, Lopez B et al (2011) Diastolic tissue Doppler indexes correlate with the degree of collagen expression and cross-linking in heart failure and normal ejection fraction. J Am Coll Cardiol 57(8):977–985

    Article  CAS  PubMed  Google Scholar 

  15. Aoki T, Fukumoto Y, Sugimura K et al (2011) Prognostic impact of myocardial interstitial fibrosis in non-ischemic heart failure—comparison between preserved and reduced ejection fraction heart failure. Circ J 75(11):2605–13

    Article  CAS  PubMed  Google Scholar 

  16. Collier P, Watson CJ, Voon V et al (2011) Can emerging biomarkers of myocardial remodelling identify asymptomatic hypertensive patients at risk for diastolic dysfunction and diastolic heart failure? Eur J Heart Fail 13:1087–1095

    Article  CAS  PubMed  Google Scholar 

  17. Boyle AJ, Yeghiazarians Y, Shih H et al (2011) Myocardial production and release of MCP-1 and SDF-1 following myocardial infarction: differences between mice and man. J Transl Med 9:150

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kobayashi M, Nakamura K, Kusano KF et al (2008) Expression of monocyte chemoattractant protein-1 in idiopathic dilated cardiomyopathy. Int J Cardiol 126:427–429

    Article  PubMed  Google Scholar 

  19. Li L, Zhao Q, Kong W (2018) Extracellular matrix remodeling and cardiac fibrosis. Matrix Biol 68–69:490–506

    Article  PubMed  CAS  Google Scholar 

  20. Varga I, Kyselovic J, Galfiova P et al (2017) The non-cardiomyocyte cells of the heart. Their possible roles in exercise-induced cardiac regeneration and remodeling. Adv Exp Med Biol 999:117–136

    Article  PubMed  Google Scholar 

  21. Moore-Morris T, Guimaraes-Camboa N, Banerjee I et al (2014) Resident fibroblast lineages mediate pressure overload-induced cardiac fibrosis. J Clin Investig 124(7):2921–2934

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Bischoff J (2019) Endothelial-to-mesenchymal transition. Circ Res 124(8):1163–1165

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Ali SR, Ranjbarvaziri S, Talkhabi M, Zhao P, Subat A, Hojjat A, Kamran P, Muller AM, Volz KS, Tang Z et al (2014) Developmental heterogeneity of cardiac fibroblasts does not predict pathological proliferation and activation. Circ Res 115(7):625–635

    Article  CAS  PubMed  Google Scholar 

  24. Kanisicak O, Khalil H, Ivey MJ, Karch J, Maliken BD, Correll RN, Brody MJ, Lin SCJ, Aronow BJ, Tallquist MD et al (2016) Genetic lineage tracing defines myofibroblast origin and function in the injured heart. Nat Commun 7:12260

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Fu X, Khalil H, Kanisicak O et al (2018) Specialized fibroblast differentiated states underlie scar formation in the infarcted mouse heart. J Clin Investig 128:2127–2143

    Article  PubMed  PubMed Central  Google Scholar 

  26. Zeisberg EM, Tarnavski O, Zeisberg M, Dorfman AL, McMullen JR, Gustafsson E, Chandraker A, Yuan X, Pu WT, Roberts AB et al (2007) Endothelial-to-mesenchymal transition contributes to cardiac fibrosis. Nat Med 13(8):952–961

    Article  CAS  PubMed  Google Scholar 

  27. Jeong D, Lee MA, Li Y, Yang DK, Kho C, Oh JG, Hong G, Lee A, Song MH, LaRocca TJ et al (2016) Matricellular protein CCN5 reverses established cardiac fibrosis. J Am Coll Cardiol 67(13):1556–1568

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Charytan DM, Padera R, Helfand AM, Zeisberg M, Xu X, Liu X, Himmelfarb J, Cinelli A, Kalluri R, Zeisberg EM (2014) Increased concentration of circulating angiogenesis and nitric oxide inhibitors induces endothelial to mesenchymal transition and myocardial fibrosis in patients with chronic kidney disease. Int J Cardiol 176(1):99–109

    Article  PubMed  PubMed Central  Google Scholar 

  29. Gong H, Lyu X, Wang Q, Hu M, Zhang X (2017) Endothelial to mesenchymal transition in the cardiovascular system. Life Sci 184:95–102

    Article  CAS  PubMed  Google Scholar 

  30. Baker DW, Tsai YT, Weng H, Tang L (2014) Alternative strategies to manipulate fibrocyte involvement in the fibrotic tissue response: pharmacokinetic inhibition and the feasibility of directed-adipogenic differentiation. Acta Biomater 10(7):3108–3116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Cieslik KA, Taffet GE, Carlson S, Hermosillo J, Trial J, Entman ML (2011) Immune-inflammatory dysregulation modulates the incidence of progressive fibrosis and diastolic stiffness in the aging heart. J Mol Cell Cardiol 50(1):248–256

    Article  CAS  PubMed  Google Scholar 

  32. Huang J, Huang H, Wu M, Li J, Xie H, Zhou H, Liao E, Peng Y (2013) Connective tissue growth factor induces osteogenic differentiation of vascular smooth muscle cells through ERK signaling. Int J Mol Med 32(2):423–429

    Article  PubMed  CAS  Google Scholar 

  33. Hong KM, Belperio JA, Keane MP, Burdick MD, Strieter RM (2007) Differentiation of human circulating fibrocytes as mediated by transforming growth factor-beta and peroxisome proliferator-activated receptor gamma. J Biol Chem 282(31):22910–22920

    Article  CAS  PubMed  Google Scholar 

  34. Zhou X, Chen X, Cai JJ, Chen LZ, Gong YS, Wang LX, Gao Z, Zhang HQ, Huang WJ, Zhou H (2015) Relaxin inhibits cardiac fibrosis and endothelial-mesenchymal transition via the Notch pathway. Drug Des Dev Ther 9:4599–4611

    Article  CAS  Google Scholar 

  35. Ishii G, Sangai T, Sugiyama K, Ito T, Hasebe T, Endoh Y, Magae J, Ochiai A (2005) In vivo characterization of bone marrow-derived fibroblasts recruited into fibrotic lesions. Stem Cells 23(5):699–706

    Article  CAS  PubMed  Google Scholar 

  36. Haudek SB, Xia Y, Huebener P, Lee JM, Carlson S, Crawford JR, Pilling D, Gomer RH, Trial J, Frangogiannis NG et al (2006) Bone marrow-derived fibroblast precursors mediate ischemic cardiomyopathy in mice. Proc Natl Acad Sci USA 103(48):18284–18289

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Kramann R, Schneider RK, DiRocco DP, Machado F, Fleig S, Bondzie PA, Henderson JM, Ebert BL, Humphreys BD (2015) Perivascular Gli1+ progenitors are key contributors to injury-induced organ fibrosis. Cell Stem Cell 16(1):51–66

    Article  CAS  PubMed  Google Scholar 

  38. Bonnans C, Chou J, Werb Z (2014) Remodelling the extracellular matrix in development and disease. Nat Rev Mol Cell Biol 15(12):786–801

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Theocharis AD, Skandalis SS, Gialeli C, Karamanos NK (2016) Extracellular matrix structure. Adv Drug Deliv Rev 97:4–27

    Article  CAS  PubMed  Google Scholar 

  40. Yang H, Borg TK, Wang Z, Ma Z, Gao BZ (2014) Role of the basement membrane in regulation of cardiac electrical properties. Ann Biomed Eng 42(6):1148–1157

    Article  PubMed  PubMed Central  Google Scholar 

  41. Frangogiannis NG (2017) Fibroblasts and the extracellular matrix in right ventricular disease. Cardiovasc Res 113(12):1453–1464

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Frangogiannis NG (2019) The extracellular matrix in ischemic and nonischemic heart failure. Circ Res 125(1):117–146

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Harvey A, Montezano AC, Lopes RA, Rios F, Touyz RM (2016) Vascular fibrosis in aging and hypertension: molecular mechanisms and clinical implications. Can J Cardiol 32(5):659–668

    Article  PubMed  Google Scholar 

  44. Nguyen-Truong M, Wang Z (2018) Biomechanical properties and mechanobiology of cardiac ECM. Adv Exp Med Biol 1098:1–19

    Article  CAS  PubMed  Google Scholar 

  45. Wang J, Hoshijima M, Lam J, Zhou Z, Jokiel A, Dalton ND, Hultenby K, Ruiz-Lozano P, Ross J Jr, Tryggvason K et al (2006) Cardiomyopathy associated with microcirculation dysfunction in laminin alpha4 chain-deficient mice. J Biol Chem 281(1):213–220

    Article  CAS  PubMed  Google Scholar 

  46. Russo I, Cavalera M, Huang S, Su Y, Hanna A, Chen B, Shinde AV, Conway SJ, Graff J, Frangogiannis NG (2019) Protective effects of activated myofibroblasts in the pressure-overloaded myocardium are mediated through smad-dependent activation of a matrix-preserving program. Circ Res 124(8):1214–1227

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Naga Prasad SV, Perrino C, Rockman HA (2003) Role of phosphoinositide 3-kinase in cardiac function and heart failure. Trends Cardiovasc Med 13(5):206–212

    Article  PubMed  CAS  Google Scholar 

  48. Engelman JA, Luo J, Cantley LC (2006) The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet 7(8):606–619

    Article  CAS  PubMed  Google Scholar 

  49. Falasca M, Maffucci T (2012) Regulation and cellular functions of class II phosphoinositide 3-kinases. Biochem J 443(3):587–601

    Article  CAS  PubMed  Google Scholar 

  50. Vanhaesebroeck B, Guillermet-Guibert J, Graupera M, Bilanges B (2010) The emerging mechanisms of isoform-specific PI3K signalling. Nat Rev Mol Cell Biol 11(5):329–341

    Article  CAS  PubMed  Google Scholar 

  51. Ghigo A, Laffargue M, Li M, Hirsch E (2017) PI3K and calcium signaling in cardiovascular disease. Circ Res 121(3):282–292

    Article  CAS  PubMed  Google Scholar 

  52. Falasca M, Maffucci T (2009) Rethinking phosphatidylinositol 3-monophosphate. Biochim Biophys Acta 1793(12):1795–1803

    Article  CAS  PubMed  Google Scholar 

  53. Falasca M, Hughes WE, Dominguez V, Sala G, Fostira F, Fang MQ, Cazzolli R, Shepherd PR, James DE, Maffucci T (2007) The role of phosphoinositide 3-kinase C2alpha in insulin signaling. J Biol Chem 282(38):28226–28236

    Article  CAS  PubMed  Google Scholar 

  54. Maffucci T, Cooke FT, Foster FM, Traer CJ, Fry MJ, Falasca M (2005) Class II phosphoinositide 3-kinase defines a novel signaling pathway in cell migration. J Cell Biol 169(5):789–799

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Falasca M, Maffucci T (2007) Role of class II phosphoinositide 3-kinase in cell signalling. Biochem Soc Trans 35(Pt 2):211–214

    Article  CAS  PubMed  Google Scholar 

  56. Yoshioka K, Yoshida K, Cui H, Wakayama T, Takuwa N, Okamoto Y, Du W, Qi X, Asanuma K, Sugihara K et al (2012) Endothelial PI3K-C2alpha, a class II PI3K, has an essential role in angiogenesis and vascular barrier function. Nat Med 18(10):1560–1569

    Article  CAS  PubMed  Google Scholar 

  57. Crackower MA, Oudit GY, Kozieradzki I, Sarao R, Sun H, Sasaki T, Hirsch E, Suzuki A, Shioi T, Irie-Sasaki J et al (2002) Regulation of myocardial contractility and cell size by distinct PI3K-PTEN signaling pathways. Cell 110(6):737–749

    Article  CAS  PubMed  Google Scholar 

  58. Northcott CA, Poy MN, Najjar SM, Watts SW (2002) Phosphoinositide 3-kinase mediates enhanced spontaneous and agonist-induced contraction in aorta of deoxycorticosterone acetate-salt hypertensive rats. Circ Res 91(4):360–369

    Article  CAS  PubMed  Google Scholar 

  59. Wymann MP, Zvelebil M, Laffargue M (2003) Phosphoinositide 3-kinase signalling—which way to target? Trends Pharmacol Sci 24(7):366–376

    Article  CAS  PubMed  Google Scholar 

  60. Macrez N, Mironneau C, Carricaburu V, Quignard JF, Babich A, Czupalla C, Nurnberg B, Mironneau J (2001) Phosphoinositide 3-kinase isoforms selectively couple receptors to vascular L-type Ca(2+) channels. Circ Res 89(8):692–699

    Article  CAS  PubMed  Google Scholar 

  61. Oudit GY, Sun H, Kerfant BG, Crackower MA, Penninger JM, Backx PH (2004) The role of phosphoinositide-3 kinase and PTEN in cardiovascular physiology and disease. J Mol Cell Cardiol 37(2):449–471

    Article  CAS  PubMed  Google Scholar 

  62. Chavakis E, Carmona G, Urbich C, Gottig S, Henschler R, Penninger JM, Zeiher AM, Chavakis T, Dimmeler S (2008) Phosphatidylinositol-3-kinase-gamma is integral to homing functions of progenitor cells. Circ Res 102(8):942–949

    Article  CAS  PubMed  Google Scholar 

  63. Marui T, Fukahori H, Ito M, Kaneko Y, Maeda M, Tsujimoto S, Morokata T (2019) The PI3Kdelta selective inhibitor AS2541019 suppresses donor-specific antibody production in rat cardiac and non-human primate renal allotransplant models. Int Immunopharmacol 75:105756

    Article  CAS  PubMed  Google Scholar 

  64. Zhabyeyev P, McLean B, Patel VB, Wang W, Ramprasath T, Oudit GY (2014) Dual loss of PI3Kα and PI3Kγ signaling leads to an age-dependent cardiomyopathy. J Mol Cell Cardiol 77:155–159

    Article  CAS  PubMed  Google Scholar 

  65. Yang KC, Ku YC, Lovett M, Nerbonne JM (2012) Combined deep microRNA and mRNA sequencing identifies protective transcriptomal signature of enhanced PI3Kα signaling in cardiac hypertrophy. J Mol Cell Cardiol 53(1):101–112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Yang L, Cai X, Liu J, Jia Z, Jiao J, Zhang J, Li C, Li J, Tang XD (2013) CpG-ODN attenuates pathological cardiac hypertrophy and heart failure by activation of PI3Kα-Akt signaling. PLoS One 8(4):e62373

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. McMullen JR, Amirahmadi F, Woodcock EA, Schinke-Braun M, Bouwman RD, Hewitt KA, Mollica JP, Zhang L, Zhang Y, Shioi T et al (2007) Protective effects of exercise and phosphoinositide 3-kinase(p110alpha) signaling in dilated and hypertrophic cardiomyopathy. Proc Natl Acad Sci USA 104(2):612–617

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Yano N, Tseng A, Zhao TC, Robbins J, Padbury JF, Tseng YT (2008) Temporally controlled overexpression of cardiac-specific PI3Kalpha induces enhanced myocardial contractility—a new transgenic model. Am J Physiol Heart Circ Physiol 295(4):H1690–H1694

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Liang W, Oudit GY, Patel MM, Shah AM, Woodgett JR, Tsushima RG, Ward ME, Backx PH (2010) Role of phosphoinositide 3-kinase α, protein kinase C, and L-type Ca2+ channels in mediating the complex actions of angiotensin II on mouse cardiac contractility. Hypertension 56(3):422–429

    Article  CAS  PubMed  Google Scholar 

  70. Damilano F, Franco I, Perrino C, Schaefer K, Azzolino O, Carnevale D, Cifelli G, Carullo P, Ragona R, Ghigo A, Perino A, Lembo G, Hirsch E (2011) Distinct effects of leukocyte and cardiac phosphoinositide 3-kinase γ activity in pressure overload-induced cardiac failure. Circulation 123(4):391–399

    Article  CAS  PubMed  Google Scholar 

  71. Song LF, Jiang W, Qing Y, Hu XH, Li Y, Tong QY, Wu XH (2011) The antagonistic effect of PI3K-gamma inhibitor AS605240 on cardiac hypertrophy and cardiac fibrosis induced by isoproterenol in rats. Chin Sichuan Da Xue Xue Bao Yi Xue Ban 42(4):471–4

    CAS  Google Scholar 

  72. McMullen JR, Shioi T, Zhang L, Tarnavski O, Sherwood MC, Kang PM, Izumo S (2003) Phosphoinositide 3-kinase(p110alpha) plays a critical role for the induction of physiological, but not pathological, cardiac hypertrophy. Proc Natl Acad Sci USA 100(21):12355–12360

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Maffei A, Cifelli G, Carnevale R, Iacobucci R, Pallante F, Fardella V, Fardella S, Hirsch E, Lembo G, Carnevale D (2017) PI3Kγ inhibition protects against diabetic cardiomyopathy in mice. Rev Esp Cardiol (Engl Ed) 70(1):16–24

    Article  Google Scholar 

  74. Unsöld B, Bremen E, Didié M, Hasenfuss G, Schäfer K (2015) Differential PI3K signal transduction in obesity-associated cardiac hypertrophy and response to ischemia. Obesity (Silver Spring) 23(1):90–99

    Article  CAS  Google Scholar 

  75. Perino A, Ghigo A, Ferrero E, Morello F, Santulli G, Baillie GS, Damilano F, Dunlop AJ, Pawson C, Walser R et al (2011) Integrating cardiac PIP3 and cAMP signaling through a PKA anchoring function of p110gamma. Mol Cell 42(1):84–95

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Damilano F, Perino A, Hirsch E (2010) PI3K kinase and scaffold functions in heart. Ann N Y Acad Sci 1188:39–45

    Article  CAS  PubMed  Google Scholar 

  77. Patrucco E, Notte A, Barberis L, Selvetella G, Maffei A, Brancaccio M, Marengo S, Russo G, Azzolino O, Rybalkin SD et al (2004) PI3Kgamma modulates the cardiac response to chronic pressure overload by distinct kinase-dependent and -independent effects. Cell 118(3):375–387

    Article  CAS  PubMed  Google Scholar 

  78. Oudit GY, Crackower MA, Eriksson U, Sarao R, Kozieradzki I, Sasaki T, Irie-Sasaki J, Gidrewicz D, Rybin VO, Wada T et al (2003) Phosphoinositide 3-kinase gamma-deficient mice are protected from isoproterenol-induced heart failure. Circulation 108(17):2147–2152

    Article  CAS  PubMed  Google Scholar 

  79. Rose RA, Kabir MG, Backx PH (2007) Altered heart rate and sinoatrial node function in mice lacking the cAMP regulator phosphoinositide 3-kinase-gamma. Circ Res 101(12):1274–1282

    Article  CAS  PubMed  Google Scholar 

  80. Ghigo A (2019) Cell-specific roles of p110beta in myocardial ischaemia. Cardiovasc Res 115(8):1264–1265

    Article  CAS  PubMed  Google Scholar 

  81. Heller R, Chang Q, Ehrlich G, Hsieh SN, Schoenwaelder SM, Kuhlencordt PJ, Preissner KT, Hirsch E, Wetzker R (2008) Overlapping and distinct roles for PI3Kbeta and gamma isoforms in S1P-induced migration of human and mouse endothelial cells. Cardiovasc Res 80(1):96–105

    Article  CAS  PubMed  Google Scholar 

  82. Guillermet-Guibert J, Bjorklof K, Salpekar A, Gonella C, Ramadani F, Bilancio A, Meek S, Smith AJ, Okkenhaug K, Vanhaesebroeck B (2008) The p110beta isoform of phosphoinositide 3-kinase signals downstream of G protein-coupled receptors and is functionally redundant with p110gamma. Proc Natl Acad Sci USA 105(24):8292–8297

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Lin Z, Zhou P, von Gise A, Gu F, Ma Q, Chen J, Guo H, van Gorp PR, Wang DZ, Pu WT (2015) Pi3kcb links Hippo-YAP and PI3K-AKT signaling pathways to promote cardiomyocyte proliferation and survival. Circ Res 116(1):35–45

    Article  CAS  PubMed  Google Scholar 

  84. Dou Z, Chattopadhyay M, Pan JA, Guerriero JL, Jiang YP, Ballou LM, Yue Z, Lin RZ, Zong WX (2010) The class IA phosphatidylinositol 3-kinase p110-beta subunit is a positive regulator of autophagy. J Cell Biol 191(4):827–843

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Chen X, Zhabyeyev P, Azad AK, Wang W, Minerath RA, DesAulniers J, Grueter CE, Murray AG, Kassiri Z, Vanhaesebroeck B et al (2019) Endothelial and cardiomyocyte PI3Kbeta divergently regulate cardiac remodelling in response to ischaemic injury. Cardiovasc Res 115(8):1343–1356

    Article  CAS  PubMed  Google Scholar 

  86. Tang Y, Zhang Y, Chen Y, Xiang Y, Xie Y (2015) Role of the microRNA, miR-206, and its target PIK3C2alpha in endothelial progenitor cell function—potential link with coronary artery disease. FEBS J 282(19):3758–3772

    Article  CAS  PubMed  Google Scholar 

  87. Domin J, Pages F, Volinia S, Rittenhouse SE, Zvelebil MJ, Stein RC, Waterfield MD (1997) Cloning of a human phosphoinositide 3-kinase with a C2 domain that displays reduced sensitivity to the inhibitor wortmannin. Biochem J 326(Pt 1):139–147

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Brown RA, Ho LK, Weber-Hall SJ, Shipley JM, Fry MJ (1997) Identification and cDNA cloning of a novel mammalian C2 domain-containing phosphoinositide 3-kinase, HsC2-PI3K. Biochem Biophys Res Commun 233(2):537–544

    Article  CAS  PubMed  Google Scholar 

  89. Braccini L, Ciraolo E, Campa CC, Perino A, Longo DL, Tibolla G, Pregnolato M, Cao Y, Tassone B, Damilano F et al (2015) PI3K-C2gamma is a Rab5 effector selectively controlling endosomal Akt2 activation downstream of insulin signalling. Nat Commun 6:7400

    Article  CAS  PubMed  Google Scholar 

  90. Rozycka M, Lu YJ, Brown RA, Lau MR, Shipley JM, Fry MJ (1998) cDNA cloning of a third human C2-domain-containing class II phosphoinositide 3-kinase, PI3K-C2gamma, and chromosomal assignment of this gene (PIK3C2G) to 12p12. Genomics 54(3):569–574

    Article  CAS  PubMed  Google Scholar 

  91. Ghigo A, Li M (2015) Phosphoinositide 3-kinase: friend and foe in cardiovascular disease. Front Pharmacol 6:169

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. Eun LY, Song BW, Cha MJ, Song H, Kim IK, Choi E, Chang W, Lim S, Choi EJ, Ham O et al (2010) Overexpression of phosphoinositide-3-kinase class II alpha enhances mesenchymal stem cell survival in infarcted myocardium. Biochem Biophys Res Commun 402(2):272–279

    Article  CAS  PubMed  Google Scholar 

  93. Tibolla G, Pineiro R, Chiozzotto D, Mavrommati I, Wheeler AP, Norata GD, Catapano AL, Maffucci T, Falasca M (2013) Class II phosphoinositide 3-kinases contribute to endothelial cells morphogenesis. PLoS One 8(1):e53808

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Jaber N, Zong WX (2012) Class III PI3K Vps34 plays an essential role in autophagy and in heart and liver function. Proc Natl Acad Sci USA 109(6):2003–2008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Kihara A, Noda T, Ishihara N, Ohsumi Y (2001) Two distinct Vps34 phosphatidylinositol 3-kinase complexes function in autophagy and carboxypeptidase Y sorting in Saccharomyces cerevisiae. J Cell Biol 152(3):519–530

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Yang R, Song Z, Wu S, Wei Z, Xu Y, Shen X (2018) Toll-like receptor 4 contributes to a myofibroblast phenotype in cardiac fibroblasts and is associated with autophagy after myocardial infarction in a mouse model. Atherosclerosis 279:23–31

    Article  CAS  PubMed  Google Scholar 

  97. Ren Z, Xiao W, Zeng Y, Liu MH, Li GH, Tang ZH, Qu SL, Hao YM, Yuan HQ, Jiang ZS (2019) Fibroblast growth factor-21 alleviates hypoxia/reoxygenation injury in H9c2 cardiomyocytes by promoting autophagic flux. Int J Mol Med 43(3):1321–1330

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Yu P, Zhang Y, Li C, Li Y, Jiang S, Zhang X, Ding Z, Tu F, Wu J, Gao X et al (2015) Class III PI3K-mediated prolonged activation of autophagy plays a critical role in the transition of cardiac hypertrophy to heart failure. J Cell Mol Med 19(7):1710–1719

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Lin S, Wang Y, Zhang X, Kong Q, Li C, Li Y, Ding Z, Liu L (2016) HSP27 alleviates cardiac aging in mice via a mechanism involving antioxidation and mitophagy activation. Oxid Med Cell Longev. https://doi.org/10.1155/2016/2586706

    Article  PubMed  PubMed Central  Google Scholar 

  100. Lu Q, Yao Y, Hu Z, Hu C, Song Q, Ye J, Xu C, Wang AZ, Chen Q, Wang QK (2016) Angiogenic factor AGGF1 activates autophagy with an essential role in therapeutic angiogenesis for heart disease. PLoS Biol 14(8):e1002529

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  101. Abeyrathna P, Su Y (2015) The critical role of Akt in cardiovascular function. Vasc Pharmacol 74:38–48

    Article  CAS  Google Scholar 

  102. Yao H, Han X, Han X (2014) The cardioprotection of the insulin-mediated PI3K/Akt/mTOR signaling pathway. Am J Cardiovasc Drugs 14(6):433–442

    Article  CAS  PubMed  Google Scholar 

  103. Hanada M, Feng J, Hemmings BA (2004) Structure, regulation and function of PKB/AKT—a major therapeutic target. Biochim Biophys Acta 1697(1–2):3–16

    Article  CAS  PubMed  Google Scholar 

  104. Hers I, Vincent EE, Tavare JM (2011) Akt signalling in health and disease. Cell Signal 23(10):1515–1527

    Article  CAS  PubMed  Google Scholar 

  105. DeBosch B, Sambandam N, Weinheimer C, Courtois M, Muslin AJ (2006) Akt2 regulates cardiac metabolism and cardiomyocyte survival. J Biol Chem 281(43):32841–32851

    Article  CAS  PubMed  Google Scholar 

  106. Fernandez-Hernando C, Ackah E, Yu J, Suarez Y, Murata T, Iwakiri Y, Prendergast J, Miao RQ, Birnbaum MJ, Sessa WC (2007) Loss of Akt1 leads to severe atherosclerosis and occlusive coronary artery disease. Cell Metab 6(6):446–457

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Latronico MV, Costinean S, Lavitrano ML, Peschle C, Condorelli G (2004) Regulation of cell size and contractile function by AKT in cardiomyocytes. Ann N Y Acad Sci 1015:250–260

    Article  CAS  PubMed  Google Scholar 

  108. Nagoshi T, Matsui T, Aoyama T, Leri A, Anversa P, Li L, Ogawa W, del Monte F, Gwathmey JK, Grazette L et al (2005) PI3K rescues the detrimental effects of chronic Akt activation in the heart during ischemia/reperfusion injury. J Clin Investig 115(8):2128–2138

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Ma ZG, Yuan YP, Zhang X, Xu SC, Wang SS, Tang QZ (2017) Piperine attenuates pathological cardiac fibrosis via PPAR-γ/AKT pathways. EBioMedicine 18:179–187

    Article  PubMed  PubMed Central  Google Scholar 

  110. Derynck R, Zhang YE (2003) Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature 425:577–584

    Article  CAS  PubMed  Google Scholar 

  111. Wei WY, Ma ZG, Xu SC, Zhang N, Tang QZ (2016) Pioglitazone protected against cardiac hypertrophy via inhibiting AKT/GSK3β and MAPK signaling pathways. PPAR Res 2016:1–11

    Article  CAS  Google Scholar 

  112. Hardt SE, Sadoshima J (2002) Glycogen synthase kinase-3beta: a novel regulator of cardiac hypertrophy and development. Circ Res 90:1055–1063

    Article  CAS  PubMed  Google Scholar 

  113. Chiang GG, Abraham RT (2005) Phosphorylation of mammalian target of rapamycin (mTOR) at Ser-2448 is mediated by p70S6 kinase. J Biol Chem 280(27):25485–25490

    Article  CAS  PubMed  Google Scholar 

  114. Sekulić A, Hudson CC, Homme JL, Yin P, Otterness DM, Karnitz LM, Abraham RT (2000) A direct linkage between the phosphoinositide 3-kinase-AKT signaling pathway and the mammalian target of rapamycin in mitogenstimulated and transformed cells. Cancer Res 60:3504–3513

    PubMed  Google Scholar 

  115. Shi B, Ma M, Zheng Y, Pan Y, Lin X (2019) mTOR and Beclin1: two key autophagy-related molecules and their roles in myocardial ischemia/reperfusion injury. J Cell Physiol 234(8):12562–12568

    Article  CAS  PubMed  Google Scholar 

  116. Baretic D, Williams RL (2014) The structural basis for mTOR function. Semin Cell Dev Biol 36:91–101

    Article  CAS  PubMed  Google Scholar 

  117. Samidurai A, Kukreja RC, Das A (2018) Emerging role of mTOR signaling-related miRNAs in cardiovascular diseases. Oxid Med Cell Longev. https://doi.org/10.1155/2018/6141902

    Article  PubMed  PubMed Central  Google Scholar 

  118. Singh VP, Baker KM, Kumar R (2008) Activation of the intracellular renin-angiotensin system in cardiac fibroblasts by high glucose: role in extracellular matrix production. Am J Physiol Heart Circ Physiol 294:H1675–H1684

    Article  CAS  PubMed  Google Scholar 

  119. Finckenberg P, Inkinen K, Ahonen J, Merasto S, Louhelainen M, Vapaatalo H, Müller D, Ganten D, Luft F, Mervaala E (2003) Angiotensin II induces connective tissue growth factor gene expression via calcineurin-dependent pathways. Am J Pathol 163(1):355–366

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Mitra A, Luna JI, Marusina AI, Merleev A, Kundu-Raychaudhuri S, Fiorentino D, Raychaudhuri SP, Maverakis E (2015) Dual mTOR inhibition is required to prevent TGF-β-mediated fibrosis: implications for scleroderma. J Investig Dermatol 135(11):2873–2876

    Article  CAS  PubMed  Google Scholar 

  121. Martínez-Martínez E, Jurado-López R, Valero-Muñoz M, Bartolomé MV, Ballesteros S, Luaces M, Cachofeiro V (2014) Leptin induces cardiac fibrosis through galectin-3, mTOR and oxidative stress. J Hypertens 32(5):1104–1114

    Article  PubMed  CAS  Google Scholar 

  122. Takahashi-Yanaga F (2018) Roles of glycogen synthase kinase-3 (GSK-3) in cardiac development and heart disease. J UOEH 40(2):147–156

    Article  CAS  PubMed  Google Scholar 

  123. Schluter KD, Goldberg Y, Taimor G, Schafer M, Piper HM (1998) Role of phosphatidylinositol 3-kinase activation in the hypertrophic growth of adult ventricular cardiomyocytes. Cardiovasc Res 40(1):174–181

    Article  CAS  PubMed  Google Scholar 

  124. Kajstura J, Urbanek K, Perl S, Hosoda T, Zheng H, Ogorek B, Ferreira-Martins J, Goichberg P, Rondon-Clavo C, Sanada F et al (2010) Cardiomyogenesis in the adult human heart. Circ Res 107(2):305–315

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. McNab TC, Tseng YT, Stabila JP, McGonnigal BG, Padbury JF (2001) Liganded and unliganded steroid receptor modulation of beta 1 adrenergic receptor gene transcription. Pediatr Res 50(5):575–580

    Article  CAS  PubMed  Google Scholar 

  126. Wadhawan R, Tseng YT, Stabila J, McGonnigal B, Sarkar S, Padbury J (2003) Regulation of cardiac beta 1-adrenergic receptor transcription during the developmental transition. Am J Physiol Heart Circ Physiol 284(6):H2146-2152

    Article  CAS  PubMed  Google Scholar 

  127. Chruscinski AJ, Rohrer DK, Schauble E, Desai KH, Bernstein D, Kobilka BK (1999) Targeted disruption of the beta2 adrenergic receptor gene. J Biol Chem 274(24):16694–16700

    Article  CAS  PubMed  Google Scholar 

  128. Rohrer DK, Chruscinski A, Schauble EH, Bernstein D, Kobilka BK (1999) Cardiovascular and metabolic alterations in mice lacking both beta1- and beta2-adrenergic receptors. J Biol Chem 274(24):16701–16708

    Article  CAS  PubMed  Google Scholar 

  129. Li F, Wang X, Bunger PC, Gerdes AM (1997) Formation of binucleated cardiac myocytes in rat heart: I. Role of actin-myosin contractile ring. J Mol Cell Cardiol 29(6):1541–1551

    Article  CAS  PubMed  Google Scholar 

  130. Guo Y, Gupte M, Umbarkar P, Singh AP, Sui JY, Force T, Lal H (2017) Entanglement of GSK-3beta, beta-catenin and TGF-beta1 signaling network to regulate myocardial fibrosis. J Mol Cell Cardiol 110:109–120

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Sundaresan NR, Bindu S, Pillai VB, Samant S, Pan Y, Huang JY, Gupta M, Nagalingam RS, Wolfgeher D, Verdin E, Gupta MP (2015) SIRT3 blocks aging-associated tissue fibrosis in mice by deacetylating and activating glycogen synthase kinase 3β. Mol Cell Biol 36(5):678–692

    Article  PubMed  CAS  Google Scholar 

  132. Lal H, Ahmad F, Zhou J, Yu JE, Vagnozzi RJ, Guo Y, Yu D, Tsai EJ, Woodgett J, Gao E, Force T (2014) Cardiac fibroblast glycogen synthase kinase-3β regulates ventricular remodeling and dysfunction in ischemic heart. Circulation 130(5):419–430

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Bujak M, Ren G, Kweon HJ, Dobaczewski M, Reddy A, Taffet G, Wang XF, Frangogiannis NG (2007) Essential role of Smad3 in infarct healing and in the pathogenesis of cardiac remodeling. Circulation 116(19):2127–2138

    Article  CAS  PubMed  Google Scholar 

  134. Accili D, Arden KC (2004) FoxOs at the crossroads of cellular metabolism, differentiation, and transformation. Cell 117(4):421–426

    Article  CAS  PubMed  Google Scholar 

  135. Skurk C, Maatz H, Kim HS, Yang J, Abid MR, Aird WC, Walsh K (2004) The Akt-regulated forkhead transcription factor FOXO3a controls endothelial cell viability through modulation of the caspase-8 inhibitor FLIP. J Biol Chem 279(2):1513–1525

    Article  CAS  PubMed  Google Scholar 

  136. Xin Z, Ma Z, Hu W, Jiang S, Yang Z, Li T, Chen F, Jia G, Yang Y (2018) FOXO1/3: potential suppressors of fibrosis. Ageing Res Rev 41:42–52

    Article  CAS  PubMed  Google Scholar 

  137. Tran H, Brunet A, Griffith EC, Greenberg ME (2003) The many forks in FOXO’s road. Sci STKE 2003(172):RE5

    Article  PubMed  Google Scholar 

  138. Sandri M, Sandri C, Gilbert A, Skurk C, Calabria E, Picard A, Walsh K, Schiaffino S, Lecker SH, Goldberg AL (2004) Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy. Cell 117(3):399–412

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Stitt TN, Drujan D, Clarke BA, Panaro F, Timofeyva Y, Kline WO, Gonzalez M, Yancopoulos GD, Glass DJ (2004) The IGF-1/PI3K/Akt pathway prevents expression of muscle atrophy-induced ubiquitin ligases by inhibiting FOXO transcription factors. Mol Cell 14(3):395–403

    Article  CAS  PubMed  Google Scholar 

  140. Hameedaldeen A, Liu J, Batres A, Graves GS, Graves DT (2014) FOXO1, TGF-beta regulation and wound healing. Int J Mol Sci 15(9):16257–16269

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  141. Zhao X, Liu Y, Du L, He L, Ni B, Hu J, Zhu D, Chen Q (2015) Threonine 32 (Thr32) of FoxO3 is critical for TGF-beta-induced apoptosis via Bim in hepatocarcinoma cells. Protein Cell 6(2):127–138

    Article  CAS  PubMed  Google Scholar 

  142. Vivar R, Humeres C, Munoz C, Boza P, Bolivar S, Tapia F, Lavandero S, Chiong M, Diaz-Araya G (2016) FoxO1 mediates TGF-beta1-dependent cardiac myofibroblast differentiation. Biochim Biophys Acta 1863(1):128–138

    Article  CAS  PubMed  Google Scholar 

  143. Ricke-Hoch M, Bultmann I, Stapel B, Condorelli G, Rinas U, Sliwa K, Scherr M, Hilfiker-Kleiner D (2014) Opposing roles of Akt and STAT3 in the protection of the maternal heart from peripartum stress. Cardiovasc Res 101(4):587–596

    Article  CAS  PubMed  Google Scholar 

  144. Pramod S, Shivakumar K (2014) Mechanisms in cardiac fibroblast growth: an obligate role for Skp2 and FOXO3a in ERK1/2 MAPK-dependent regulation of p27kip1. Am J Physiol Heart Circ Physiol 306(6):H844-855

    Article  CAS  PubMed  Google Scholar 

  145. Farah C, Michel LYM, Balligand JL (2018) Nitric oxide signalling in cardiovascular health and disease. Nat Rev Cardiol 15(5):292–316

    Article  CAS  PubMed  Google Scholar 

  146. Magenta A, Cencioni C, Fasanaro P, Zaccagnini G, Greco S, Sarra-Ferraris G, Antonini A, Martelli F, Capogrossi MC (2011) miR-200c is upregulated by oxidative stress and induces endothelial cell apoptosis and senescence via ZEB1 inhibition. Cell Death Differ 18(10):1628–1639

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Sam F, Sawyer DB, Xie Z, Chang DL, Ngoy S, Brenner DA, Siwik DA, Singh K, Apstein CS, Colucci WS (2001) Mice lacking inducible nitric oxide synthase have improved left ventricular contractile function and reduced apoptotic cell death late after myocardial infarction. Circ Res 89(4):351–356

    Article  CAS  PubMed  Google Scholar 

  148. Haywood GA, Tsao PS, von der Leyen HE, Mann MJ, Keeling PJ, Trindade PT, Lewis NP, Byrne CD, Rickenbacher PR, Bishopric NH et al (1996) Expression of inducible nitric oxide synthase in human heart failure. Circulation 93(6):1087–1094

    Article  CAS  PubMed  Google Scholar 

  149. Zhang P, Xu X, Hu X, van Deel ED, Zhu G, Chen Y (2007) Inducible nitric oxide synthase deficiency protects the heart from systolic overload-induced ventricular hypertrophy and congestive heart failure. Circ Res 100(7):1089–1098

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Engineer A, Saiyin T, Greco ER, Feng Q (2019) Say NO to ROS: their roles in embryonic heart development and pathogenesis of congenital heart defects in maternal diabetes. Antioxidants (Basel) 8(10):436

    Article  CAS  Google Scholar 

  151. Stuehr DJ, Haque MM (2019) Nitric oxide synthase enzymology in the 20 years after the Nobel Prize. Br J Pharmacol 176(2):177–188

    Article  CAS  PubMed  Google Scholar 

  152. Xu KY, Huso DL, Dawson TM, Bredt DS, Becker LC (1999) Nitric oxide synthase in cardiac sarcoplasmic reticulum. Proc Natl Acad Sci USA 96(2):657–662

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Wilcox JN, Subramanian RR, Sundell CL, Tracey WR, Pollock JS, Harrison DG, Marsden PA (1997) Expression of multiple isoforms of nitric oxide synthase in normal and atherosclerotic vessels. Arterioscler Thromb Vasc Biol 17(11):2479–2488

    Article  CAS  PubMed  Google Scholar 

  154. Balligand JL, Ungureanu-Longrois D, Simmons WW, Pimental D, Malinski TA, Kapturczak M, Taha Z, Lowenstein CJ, Davidoff AJ, Kelly RA et al (1994) Cytokine-inducible nitric oxide synthase (iNOS) expression in cardiac myocytes. Characterization and regulation of iNOS expression and detection of iNOS activity in single cardiac myocytes in vitro. J Biol Chem 269(44):27580–27588

    Article  CAS  PubMed  Google Scholar 

  155. de Vera ME, Shapiro RA, Nussler AK, Mudgett JS, Simmons RL, Morris SM Jr, Billiar TR, Geller DA (1996) Transcriptional regulation of human inducible nitric oxide synthase (NOS2) gene by cytokines: initial analysis of the human NOS2 promoter. Proc Natl Acad Sci USA 93(3):1054–1059

    Article  PubMed  PubMed Central  Google Scholar 

  156. Pautz A, Art J, Hahn S, Nowag S, Voss C, Kleinert H (2010) Regulation of the expression of inducible nitric oxide synthase. Nitric Oxide 23(2):75–93

    Article  CAS  PubMed  Google Scholar 

  157. Menshikova EB, Zenkov NK, Reutov VP (2000) Nitric oxide and NO-synthases in mammals in different functional states. Biochemistry (Mosc) 65(4):409–426

    CAS  Google Scholar 

  158. Boehm M, Novoyatleva T, Kojonazarov B, Veit F, Weissmann N, Ghofrani HA, Seeger W, Schermuly RT (2019) Nitric oxide synthase 2 induction promotes right ventricular fibrosis. Am J Respir Cell Mol Biol 60(3):346–356

    Article  CAS  PubMed  Google Scholar 

  159. Kazakov A, Hall R, Jagoda P, Bachelier K, Müller-Best P, Semenov A, Lammert F, Böhm M, Laufs U (2013) Inhibition of endothelial nitric oxide synthase induces and enhances myocardial fibrosis. Cardiovasc Res 100(2):211–221

    Article  CAS  PubMed  Google Scholar 

  160. Porter JJ, Jang HS, Haque MM, Stuehr DJ, Mehl RA (2020) Tyrosine nitration on calmodulin enhances calcium-dependent association and activation of nitric-oxide synthase. J Biol Chem 295(8):2203–2211

    Article  CAS  PubMed  Google Scholar 

  161. Nattel S (2017) Molecular and cellular mechanisms of atrial fibrosis in atrial fibrillation. JACC Clin Electrophysiol 3(5):425–435

    Article  PubMed  Google Scholar 

  162. Aikawa R, Nawano M, Gu Y, Katagiri H, Asano T, Zhu W, Nagai R, Komuro I (2000) Insulin prevents cardiomyocytes from oxidative stress-induced apoptosis through activation of PI3 kinase/Akt. Circulation 102(23):2873–2879

    Article  CAS  PubMed  Google Scholar 

  163. Sangawa A, Shintani M, Yamao N, Kamoshida S (2014) Phosphorylation status of Akt and caspase-9 in gastric and colorectal carcinomas. Int J Clin Exp Pathol 7(6):3312–3317

    PubMed  PubMed Central  Google Scholar 

  164. Zhang R, Luo D, Miao R, Bai L, Ge Q, Sessa WC, Min W (2005) Hsp90-Akt phosphorylates ASK1 and inhibits ASK1-mediated apoptosis. Oncogene 24(24):3954–3963

    Article  CAS  PubMed  Google Scholar 

  165. Walker EH, Pacold ME, Perisic O, Stephens L, Hawkins PT, Wymann MP, Williams RL (2000) Structural determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin, and staurosporine. Mol Cell 6(4):909–919

    Article  CAS  PubMed  Google Scholar 

  166. Chakrabarty A, Sanchez V, Kuba MG et al (2012) Feedback upregulation ofHER3(ErbB3) expression and activity attenuates antitumor effect ofPI3K inhibitors. Proc Natl Acad Sci USA 109(8):2718–2723

    Article  CAS  PubMed  Google Scholar 

  167. Matulonis U, Vergote I, Backes F et al (2015) Phase II study of the PI3K inhibitor pilaralisib (SAR245408; XL147) in patients with advanced or recurrent endometrial carcinoma. Gynecol Oncol 136(2):246–253

    Article  CAS  PubMed  Google Scholar 

  168. Janet C (2016) PI3K inhibitor improves PFS in BELLE-2 trial. Cancer Discov 6(2):115–116. https://doi.org/10.1158/2159-8290.CD-NB2015-176 

  169. Luo Y, Shoemaker AR, Liu X, Woods KW, Thomas SA, de Jong R, Han EK, Li T, Stoll VS, Powlas JA, Oleksijew A, Mitten MJ, Shi Y, Guan R, McGonigal TP, Klinghofer V, Johnson EF, Leverson JD, Bouska JJ, Mamo M, Smith RA, Gramling-Evans EE, Zinker BA, Mika AK, Nguyen PT, Oltersdorf T, Rosenberg SH, Li Q, Giranda VL (2005) Potent and selective inhibitors of Akt kinases slow the progress of tumors in vivo. Mol Cancer Ther 4(6):977–986

    Article  CAS  PubMed  Google Scholar 

  170. Cherrin C, Haskell K, Howell B, Jones R, Leander K, Robinson R, Watkins A, Bilodeau M, Hoffman J, Sanderson P, Hartman G, Mahan E, Prueksaritanont T, Jiang G, She QB, Rosen N, Sepp-Lorenzino L, Defeo-Jones D, Huber HE (2010) An allosteric Akt inhibitor effectively blocks Akt signaling and tumor growth with only transient effects on glucose and insulin levels in vivo. Cancer Biol Ther 9(7):493–503

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Fei Yang for exceptional technical assistance.

Author information

Authors and Affiliations

Authors

Contributions

WQ and LC contributed to the conception and design of this study. WQ organized the figures. LC wrote the manuscript. LC and IYM edited and revised the manuscript. All authors approved the final version of the manuscript submitted for publication.

Corresponding author

Correspondence to Linghui Cao.

Ethics declarations

Conflict of interest

The authors declare that there are no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Qin, W., Cao, L. & Massey, I.Y. Role of PI3K/Akt signaling pathway in cardiac fibrosis. Mol Cell Biochem 476, 4045–4059 (2021). https://doi.org/10.1007/s11010-021-04219-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-021-04219-w

Keywords

Navigation