Regulatory Role of Some Protein Kinases in Signal Transduction Pathways in Heart Health and Disease
Abstract
Various protein kinases including protein kinase A (PKA), Ca2+-calmodulin kinase (CaMK), phosphoinositide 3-kinase (PI3K), protein kinase C (PKC) and mitogen-activated protein kinase (MAPK: ERK1/2, p38-MAPK and JNK) are integral part of different signal transduction pathways, which are known to regulate cardiac structure, function and metabolism. In addition, these signal transducing proteins are involved in the regulation of cation transport, cellular growth, gene expression, apoptosis and fibrosis by modifying the function of different target sites of subcellular organelles in the myocardium. However, the information regarding these signal transducing molecules is scattered and mechanisms of their involvement in diverse regulatory processes are poorly understood. While PKA, CaMK, PI3K and PKC are activated by different hormones and mechanical stimuli, MAPKs are activated by growth factors and some cellular stresses such as oxidative stress, inflammation and Ca2+-overload. Each type of these protein kinases is expressed in the form of two or more isozymes showing different biochemical characteristics and distinct biological functions. It has been demonstrated that all specific isoforms of these kinases produce both beneficial and detrimental effects on the heart, which are dependent upon the intensity and duration of stimulus for their activation. While PKA, PKC and CaMK are mainly involved in augmenting cardiac function as well as inducing cardiac hypertrophy and arrhythmias, PI3K is mainly involved in maintaining β-adrenoceptor function and inducing inflammation as well as arrhythmias. On the other hand, ERK1/2 mainly participate in the genesis of cardiac hypertrophy and cytoprotection whereas p38-MAPK and JNK are primarily involved in cardiac dysfunction, apoptosis and fibrosis. Since the activities of most protein kinases are increased under prolonged pathological conditions, a wide variety of their inhibitors have been shown to produce beneficial effects. However, extensive research needs to be carried out to understand the pathophysiology of different isoforms of each protein kinase as well as for the development of their isoform-specific inhibitors.
References
1. Taylor SS, Buechler JA, Yonemoto W. cAMP-dependent protein kinase: Framework for a diverse family of regulatory enzymes. Annu Rev Biochem 1990;59:971-1005.
2. Dhalla NS, Wang J. Role of protein kinase C and protein kinase A in heart function in health and disease. Exp Clin Cardiol 1999;4:7-14.
3. Kikkawa U, Nishizuka Y. The role of protein kinase C in transmembrane signalling. Annu Rev Cell Biol 1986;2:149–78.
4. Mellor H, Parker PJ. The extended protein kinase C superfamily. Biochem J 1998;332:281-92.
5. Hook SS, Means AR. Ca2+/CaM-dependent kinases: From activation to function. Annu Rev Pharmacol Toxicol 2001;41:471-505.
6. Hudmon A, Schulman H. Neuronal Ca2+/calmodulin-dependent protein kinase II: the role of structure and autoregulation in cellular function. Annu Rev Biochem 2002;71:473–510.
7. Walker EH, Perisic O, Ried C, Stephens L, Williams RL. Structural insights into phosphoinositide 3-kinases catalysis and signaling. Nature 1999; 402:313-20.
8. Djordjevic S, Driscoll PC. Structural insight into substrate specificity and regulatory mechanisms of phosphoinositide 3-kinases. Trends Biochem Sci 2002;27:426–32.
9. Chan TO, Rittenhouse SE, Tsichlis PN. AKT/PKB and other D3 phosphoinositide-regulated kinases: Kinase activation by phosphoinositide-dependent phosphorylation. Annu Rev Biochem 1999;68:965-1014.
10. Zhang W, Elimban V, Nijjar MS, Gupta SK, Dhalla NS. Role of mitogen-activated protein kinase in cardiac hypertrophy and heart failure. Exp Clin Cardiol 2003;8:173-83.
11. Krishna M, Narang H. The complexity of mitogen-activated protein kinases (MAPKs) made simple. Cell Mol Life Sci 2008;65:3525–44.
12. Bhullar SK, Shah AK, Dhalla NS. Role of angiotensin II in the development of subcellular remodeling in heart failure. Explor Med 2021;2:352-71.
13. Bhullar SK, Dhalla, NS. Angiotensin II-induced signal transduction mechanisms for cardiac hypertrophy. Cells 2022;11: 3336. doi: 10.3390/cells11213336.
14. Bhullar SK, Shah AK, Dhalla, NS. Mechanisms for the development of heart failure and improvement of cardiac function by angiotensin-converting enzyme inhibitors. Scr Med 2022;53:51-76.
15. Bogoyevitch MA, Sugden PH. The role of protein kinases in adaptational growth of the heart. Int J Biochem Cell Biol 1996;28:1–12.
16. Sugden PH, Bogoyevitch, MA. Intracellular signaling through protein kinases in the heart. Cardiovasc Res 1995;30:478-92.
17. Dhalla NS, Muller AL. Protein kinase as drug development targets for heart disease therapy. Pharmaceuticals 2010;3:2111-45.
18. Turnham RE, Scott JD. Protein kinase A catalytic subunit isoform PRKACA; History, function and physiology. Gene 2016;577:101–8.
19. Heldin C-H. Dimerization of cell surface receptors in signal transduction. Cell 1995;80:213–23.
20. Di Benedetto G, Zoccarato A, Lissandron V, Terrin A, Li X, Houslay MD, et al. Protein kinase A type I as type II define distinct intercellur signaling compartments. Circ Res 2008;103:836-44.
21. Baryshnikova OK, Li MX, Sykes BD. Modulation of cardiac troponin C function by the cardiac-specific N-terminus of troponin I: influence of PKA phosphorylation and involvement in cardiomyopathies. J Mol Biol 2008;375:735–51.
22. Shaffer JF, Kensler RW, Harris SP. The myosin-binding protein C motif binds to F-actin in a phosphorylation-sensitive manner. J Biol Chem 2009;284:12318–27.
23. Jones PP, Meng X, Xiao B, Cai S, Bolstad J, Wagenknecht T, et al. Localization of PKA phosphorylation site, Ser2030, in the three-dimensional structure of cardiac ryanodine receptor. Biochem J 2008;410:261–70.
24. Hakim K, Fischer M, Günnicker M, Poenicke K, Zerkowski HR, Brodde OE. Functional role of β2-adrenoceptors in the transplanted human heart. J Cardiovasc Pharmacol 1997;30:811–6.
25. Surdo NC, Berrera M, Koschinski A, Brescia M, Machado MR, Carr C, et al. FRET biosensor uncovers cAMP nano-domains at β-adrenergic targets that dictate precise tuning of cardiac contractility. Nat Commun 2017;8:1–14.
26. Böhm M, Reiger B, Schwinger RH, Erdmann E. cAMP concentrations, cAMP dependent protein kinase activity, and phospholamban in non-failing and failing myocardium. Cardiovasc Res 1994;28:1713–9.
27. Mattiazzi A, Hove-Madsen L, Bers DM. Protein kinase inhibitors reduce SR Ca transport in permeabilized cardiac myocytes. Am J Physiol Heart Circ Physiol 1994;267:H812–20.
28. Robinet A, Hoizey G, Millart H. PI 3-kinase, protein kinase C, and protein kinase A are involved in the trigger phase of β1-adrenergic preconditioning. Cardiovasc Res 2005;66:530–42.
29. Wehrens XH, Lehnart SE, Reiken S, Vest JA, Wronska A, Marks AR. Ryanodine receptor/calcium release channel PKA phosphorylation: a critical mediator of heart failure progression. Proc Natl Acad Sci 2006;103:511–8.
30. Ogrodnik J, Niggli E. Increased Ca2+ leak and spatiotemporal coherence of Ca2+ release in cardiomyocytes during β‐adrenergic stimulation. J Physiol 2010;588:225–42.
31. Sadayappan S, Gulick J, Osinska H, Corbalán R, Foncea R, Ebensperger R, et al. A critical function for Ser-282 in cardiac Myosin binding protein-C phosphorylation and cardiac function. Circ Res 2011;109:141–50.
32. Piddo AM, Sánchez MI, Sapag-Hagar M, Corbalán R, Foncea R, Ebensperger R, et al. Cyclic AMP-dependent protein kinase and mechanical heart function in ventricular hypertrophy induced by pressure overload or secondary to myocardial infarction. J Mol Cell Cardiol 1996;28:1073–83.
33. Kentish JC, McCloskey DT, Layland J, Palmer S, Leiden JM, Martin AF, et al. Phosphorylation of troponin I by protein kinase A accelerates relaxation and crossbridge cycle kinetics in mouse ventricular muscle. Circ Res 2001;88:1059–65.
34. Zhang R, Zhao J, Mandveno A, Potter JD. Cardiac troponin I phosphorylation increases the rate of cardiac muscle relaxation. Circ Res 1995;76:1028–35.
35. Takimoto E, Soergel DG, Janssen PM, Stull LB, Kass DA, Murphy AM. Frequency-and afterload-dependent cardiac modulation in vivo by troponin I with constitutively active protein kinase A phosphorylation sites. Circ Res 2004;94:496–504.
36. Sanada S, Kitakaze M, Papst PJ, Asanuma H, Node K, Takashima S, et al. Cardioprotective effect afforded by transient exposure to phosphodiesterase III inhibitors: the role of protein kinase A and p38 mitogen-activated protein kinase. Circulation 2001;104:705–10.
37. Zhang F, Hu Y, Huang P, Toleman CA, Paterson AJ, Kudlow JE. Proteasome function is regulated by cyclic AMP-dependent protein kinase through phosphorylation of Rpt6. J Biol Chem 2007;282:22460–71.
38. Zhao ZQ, Velez DA, Wang NP, Hewan-Lowe KO, Nakamura M, Guyton RA, et al. Progressively developed myocardial apoptotic cell death during late phase of reperfusion. Apoptosis 2001;6:279–90.
39. Saraste A, Pulkki K, Kallajoki M, Heikkilä P, Laine P, Mattila S, et al. Cardiomyocyte apoptosis and progression of heart failure to transplantation. Eur J Clin Invest 1999;29:380-6.
40. Makaula S, Lochner A, Genade S, Sack MN, Awan MM, Opie LH. H-89, a non-specific inhibitor of protein kinase A, promotes post-ischemic cardiac contractile recovery and reduces infarct size. J Cardiovasc Pharmacol 2005;45:341–7.
41. Hudmon A, Schulman H. Structure–function of the multifunctional Ca2+/calmodulin-dependent protein kinase II. Biochem J 2002;364:593–611.
42. Tombes RM, Faison MO, Turbeville JM. Organization and evolution of multifunctional Ca2+/CaM-dependent protein kinase genes. Gene 2003;322:17–31.
43. De Koninck P, Schulman H. Sensitivity of CaM kinase II to the frequency of Ca2+ oscillations. Science 1998;279:227–30.
44. Meyer T, Hanson PI, Stryer L, Schulman H. Calmodulin trapping by calcium-calmodulin-dependent protein kinase. Science 1992;256:1199–202.
45. Soderling TR. The Ca2+–calmodulin-dependent protein kinase cascade. Trends Biochem Sci 1999;24:232–6.
46. Netticadam T, Temsah R, Osada M, Dhalla NS. Status of Ca2+/calmodulin protein kinase phosphorylation of cardiac SR proteins in ischemia-reperfusion. Am J Physiol Cell Physiol 1999;277:C384-91.
47. Koval OM, Guan X, Wu Y, Joiner ML, Gao Z, Chen B, et al. CaV1.2 β-subunit coordinates CaMKII-triggered cardiomyocyte death and afterdepolarizations. Proc Natl Acad Sci 2010;107:4996–5000.
48. Swaminathan PD, Purohit A, Soni S, Voigt N, Singh MV, Glukhov AV, et al. Oxidized CaMKII causes cardiac sinus node dysfunction in mice. J Clin Invest 2011;121:3277–88.
49. Kolodziej SJ, Hudmon A, Waxham MN, Stoops JK. Three-dimensional reconstructions of calcium/calmodulin-dependent (CaM) kinase IIα and truncated CaM kinase IIα reveal a unique organization for its structural core and functional domains. J Biol Chem 2000;275:14354–9.
50. Salas MA, Valverde CA, Sánchez G, Said M, Rodriguez JS, Portiansky EL, et al. The signalling pathway of CaMKII-mediated apoptosis and necrosis in the ischemia/reperfusion injury. J Mol Cell Cardiol 2010;48:1298–306.
51. Xie L-H, Chen F, Karagueuzian HS, Weiss JN. Oxidative stress–induced afterdepolarizations and calmodulin kinase II signaling. Circ Res 2009;104:79–86.
52. Maier LS, Bers DM. Role of Ca2+/calmodulin-dependent protein kinase (CaMK) in excitation–contraction coupling in the heart. Cardiovasc Res 2007;73:631–40.
53. Wagner S, Dybkova N, Rasenack EC, Jacobshagen C, Fabritz L, Kirchhof P, et al. Ca2+/calmodulin-dependent protein kinase II regulates cardiac Na+ channels. J Clin Invest 2006;116:3127–38.
54. Wu Y, Roden DM, Anderson ME. Calmodulin kinase inhibition prevents development of the arrhythmogenic transient inward current. Circ Res 1999;84:906–12.
55. Wu Y, Temple J, Zhang R, Dzhura I, Zhang W, Trimble R, et al. Calmodulin kinase II and arrhythmias in a mouse model of cardiac hypertrophy. Circulation 2002;106:1288–93.
56. Zhang R, Khoo MS, Wu Y, Yang Y, Grueter CE, Ni G, et al. Calmodulin kinase II inhibition protects against structural heart disease. Nat Med 2005;11:409–17.
57. Chelu MG, Sarma S, Sood S, Wang S, van Oort RJ, Skapura DG, et al. Calmodulin kinase II–mediated sarcoplasmic reticulum Ca 2+ leak promotes atrial fibrillation in mice. J Clin Invest 2009;119:1940–51.
58. van Oort RJ, McCauley MD, Dixit SS, Pereira L, Yang Y, Respress JL, et al. Ryanodine receptor phosphorylation by calcium/calmodulin-dependent protein kinase II promotes life-threatening ventricular arrhythmias in mice with heart failure. Circulation 2010;122:2669-79.
59. Zhu W, Zou Y, Shiojima I, Kudoh S, Aikawa R, Hayashi D, et al. Ca2+/calmodulin-dependent kinase II and calcineurin play critical roles in endothelin-1-induced cardiomyocyte hypertrophy. J Biol Chem 2000;275:15239–45.
60. Backs J, Backs T, Neef S, Kreusser MM, Lehmann LH, Patrick DM, et al. The δ isoform of CaM kinase II is required for pathological cardiac hypertrophy and remodeling after pressure overload. Proc Natl Acad Sci 2009;106:2342–7.
61. Ling H, Zhang T, Pereira L, Means CK, Cheng H, Gu Y, et al. Requirement for Ca 2+/calmodulin–dependent kinase II in the transition from pressure overload–induced cardiac hypertrophy to heart failure in mice. J Clin Invest 2009;119:1230–40.
62. Hagemann D, Bohlender J, Hoch B, Krause EG, Karczewski P. Expression of Ca2+/calmodulin-dependent protein kinase II δ-subunit isoforms in rats with hypertensive cardiac hypertrophy. Mol Cell Biochem 2009;220:69–76.
63. Colomer JM, Mao L, Rockman HA, Means AR. Pressure overload selectively up-regulates Ca2+/calmodulin-dependent protein kinase II in vivo. Mol Endocrinol 2003;17:183–92.
64. Peng W, Zhang Y, Zheng M, Cheng H, Zhu W, Cao CM, et al. Cardioprotection by CaMKII-δB is mediated by phosphorylation of heat shock factor 1 and subsequent expression of inducible heat shock protein 70. Circ Res 2010;106:102–10.
65. Zhu W, Woo AY, Yang D, Cheng H, Crow MT, Xiao RP. Activation of CaMKIIδC is a common intermediate of diverse death stimuli-induced heart muscle cell apoptosis. J Biol Chem 2007;282:10833–9.
66. Erickson JR, He BJ, Grumbach IM, Anderson ME. CaMKII in the cardiovascular system: sensing redox states. Physiol Rev 2011: 91;889–915.
67. Mollova MY, Katus HA, Backs J. Regulation of CaMKII signaling in cardiovascular disease. Front Pharmacol 2015; 6:178. doi: 10.3389/fphar.2015.00178.
68. Maier LS, Zhang T, Chen L, DeSantiago J, Brown JH, Bers DM. Transgenic CaMKIIδC overexpression uniquely alters cardiac myocyte Ca2+ handling: reduced SR Ca2+ load and activated SR Ca2+ release. Circ Res 2003;92:904–11.
69. Kohlhaas M, Zhang T, Seidler T, Zibrova D, Dybkova N, Steen A, et al. Increased sarcoplasmic reticulum calcium leak but unaltered contractility by acute CaMKII overexpression in isolated rabbit cardiac myocytes. Circ Res 2006;98:235–44.
70. Sag CM, Wadsack DP, Khabbazzadeh S, Abesser M, Grefe C, Neumann K, et al. Calcium/calmodulin-dependent protein kinase II contributes to cardiac arrhythmogenesis in heart failure. Circ Heart Fail 2009;2:664–75.
71. Kashiwase K, Higuchi Y, Hirotani S, Yamaguchi O, Hikoso S, Takeda T, et al. CaMKII activates ASK1 and NF-κB to induce cardiomyocyte hypertrophy. Biochem Biophys Res Commun 2005:27:136–42.
72. Takeda K, Matsuzawa A, Nishitoh H, Tobiume K, Kishida S, Ninomiya-Tsuji J, et al. Involvement of ASK1 in Ca2+-induced p38 MAP kinase activation. EMBO Rep 2004;5:161–6.
73. Passier R, Zeng H, Frey N, Naya FJ, Nicol RL, McKinsey TA, et al. CaM kinase signaling induces cardiac hypertrophy and activates the MEF2 transcription factor in vivo. J Clin Invest 2000;105:1395–406.
74. Zhang T, Johnson EN, Gu Y, Morissette MR, Sah VP, Gigena MS, et al. The cardiac-specific nuclear δB isoform of Ca2+/calmodulin-dependent protein kinase II induces hypertrophy and dilated cardiomyopathy associated with increased protein phosphatase 2A activity. J Biol Chem 2002;277:1261–7.
75. Woischwill C, Karczewski P, Bartsch H, Luther HP, Kott M, Haase H, et al. Regulation of the human atrial myosin light chain 1 promoter by Ca2+-calmodulin-dependent signaling pathways. FASEB J 2005;19:503–11.
76. Osada M, Netticadan T, Kawabata K, Tamura K, Dhalla NS. Ischemic preconditioning prevents I/R-induced alterations in SR calcium-calmodulin protein kinase II. Am J Physiol Heart Circ Physiol 2000;278:H1791–8.
77. Benter IF, Juggi JS, Khan I, Yousif MH, Canatan H, Akhtar S. Signal transduction mechanisms involved in cardiac preconditioning: role of Ras-GTPase, Ca2+/calmodulin-dependent protein kinase II and epidermal growth factor receptor. Mol Cell Biochem 2005;268:175–83.
78. Netticadan T, Temsah RM, Kawabata K, Dhalla NS. Sarcoplasmic reticulum Ca2+/calmodulin-dependent protein kinase is altered in heart failure. Circ Res 2007; 86:596–605.
79. Mishra S, Sabbah HN, Jain JC, Gupta RC. Reduced Ca2.calmodulin-dependent protein kinase activity and expression in LV myocardium of dogs with heart failure. Am J Physiol Heart Circ Physiol 2003;284:H876-83.
80. MacDonnell SM, Weisser-Thomas J, Kubo H, Hanscome M, Liu Q, et al. CaMKII negatively regulates calcineurin–NFAT signaling in cardiac myocytes. Circ Res 2009;105:316–25.
81. Kreusser MM, Lehmann LH, Keranov S, Hoting MO, Oehl U, Kohlhaas M, et al. Cardiac CaM Kinase II genes δ and γ contribute to adverse remodeling but redundantly inhibit calcineurin-induced myocardial hypertrophy. Circulation 2014;130:1262–73.
82. Newton AC. Protein kinase C: structure, function, and regulation. J Biol Chem 1995;270:28495–8.
83. Hambleton M, Hahn H, Pleger ST, Kuhn MC, Klevitsky R, Carr AN, et al. Pharmacological and gene theraphy-based inhibition of protein kinase C alpha/beta enhances contractility an attentuates heart failure. Circulation 2006;114:574-82.
84. Newton AC. Regulation of protein kinase C. Curr Opin Cell Biol 1997;9:161–7.
85. Nishizuka Y. Protein kinase C and lipid signaling for sustained cellular responses. FASEB J 1995;9:484–96.
86. Kraft AS, Anderson WB. Phorbol esters increase the amount of Ca2+, phospholipid-dependent protein kinase associated with plasma membrane. Nature 1983;301:621–3.
87. Toker A, Newton AC. Cellular signaling: pivoting around PDK-1. Cell 2000;103:185–8.
88. Gu X, Bishop SP. Increased protein kinase C and isozyme redistribution in pressure-overload cardiac hypertrophy in the rat. Circ Res 1994;75:926–31.
89. Braun MU, LaRosée P, Simonis G, Borst MM, Strasser RH. Regulation of protein kinase C isozymes in volume overload cardiac hypertrophy. Mol Cell Biochem 2004;262:135–43.
90. Paul K, Ball NA, Dorn GW, Walsh RA. Left ventricular stretch stimulates angiotensin II–mediated phosphatidylinositol hydrolysis and protein kinase C ε isoform translocation in adult guinea pig hearts. Circ Res 1997;81:643–50.
91. Wang J, Liu X, Sentex E, Takeda N, Dhalla NS. Increased expression of protein kinase C isoforms in heart failure due to myocardial infarction. Am J Physiol Heart Circ Physiol 2003;284:H2277–87.
92. Bayer AL, Heidkamp MC, Patel N, Porter M, Engman S, Samarel AM. Alterations in protein kinase C isoenzyme expression and autophosphorylation during the progression of pressure overload-induced left ventricular hypertrophy. Mol Cell Biochem 2003;242:145-52.
93. Landau D, Chayat C, Zucker N, Golomb E, Yagil C, Yagil Y, et al. Early blood pressure-independent cardiac changes in diabetic rats. J Endocrinol 2008;197:75–84.
94. Wang M, Zhang WB, Zhu JH, Fu GS, Zhou BQ. Breviscapine ameliorates cardiac dysfunction and regulates the myocardial Ca2+-cycling proteins in streptozotocin-induced diabetic rats. Acta Diabetol 2010;47:209–18.
95. Beckman JA, Goldfine AB, Gordon MB, Garrett LA, Creager MA. Inhibition of protein kinase Cβ prevents impaired endothelium-dependent vasodilation caused by hyperglycemia in humans. Circ Res 2002;90:107–11.
96. Bowling N, Walsh RA, Song G, Estridge T, Sandusky GE, Fouts RL, et al. Increased protein kinase C activity and expression of Ca2+-sensitive isoforms in the failing human heart. Circulation 1999;99:384–91.
97. Braz JC, Gregory K, Pathak A, Zhao W, Sahin B, Klevitsky R, et al. PKC-α regulates cardiac contractility and propensity toward heart failure. Nat Med 2004;10:248–54.
98. Liu Q, Chen X, Macdonnell SM, Kranias EG, Lorenz JN, Leitges M, et al. Protein kinase Cα, but not PKCβ or PKCγ, regulates contractility and heart failure susceptibility: implications for ruboxistaurin as a novel therapeutic approach. Circ Res 2009;105:194–200.
99. Connelly KA, Kelly DJ, Zhang Y, Prior DL, Advani A, Cox AJ, et al. Inhibition of protein kinase C–β by ruboxistaurin preserves cardiac function and reduces extracellular matrix production in diabetic cardiomyopathy. Circ Heart Fail 2009;2:129–37.
100. Boyle AJ, Kelly DJ, Zhang Y, Cox AJ, Gow RM, Way K, et al. Inhibition of protein kinase C reduces left ventricular fibrosis and dysfunction following myocardial infarction. J Mol Cell Cardiol 2005;39:213–21.
101. Schmidt K, Tissier R, Ghaleh B, Drogies T, Felix SB, Krieg T. Cardioprotective effects of mineralocorticoid receptor antagonists at reperfusion. Eur Heart J 2010;31:1655–62.
102. Chai W, Garrelds IM, de Vries R, Batenburg WW, van Kats JP, Danser AH. Nongenomic effects of aldosterone in the human heart: interaction with angiotensin II. Hypertension 2005;46:701–6.
103. Young LH, Balin BJ, Weis MT. Gö 6983: a fast acting protein kinase C inhibitor that attenuates myocardial ischemia/reperfusion injury. Cardiovasc Drug Rev 2005;23:255–72.
104. Peterman EE, Taormina P. Harvey M, Young LH. Gö 6983 exerts cardioprotective effects in myocardial ischemia/reperfusion. J Cardiovasc Pharmacol 2004;43:645–56.
105. 105. Omiyi D, Brue RJ, Taormina P 2nd, Harvey M, Atkinson N, Young LH. Protein kinase C βII peptide inhibitor exerts cardioprotective effects in rat cardiac ischemia/reperfusion injury. J Pharmacol Exp Ther 2005;314:542–51.
106. Phillipson A, Peterman EE, Taormina P Jr, Harvey M, Brue RJ, Atkinson N, et al. Protein kinase C-ζ inhibition exerts cardioprotective effects in ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol 2005;289:H898–907.
107. Hahn HS, Yussman MG, Toyokawa T, Marreez Y, Barrett TJ, Hilty KC, et al. Ischemic protection and myofibrillar cardiomyopathy: dose-dependent effects of in vivo δPKC inhibition. Circ Res 2002;91:741–8.
108. Inagaki K, Hahn HS, Dorn GW, Mochly-Rosen D. Additive protection of the ischemic heart ex vivo by combined treatment with δ-protein kinase C inhibitor and ε-protein kinase C activator. Circulation 2003;108:869–75.
109. Fantinelli JC, Mosca SM.Comparative effects of ischemic pre and postconditioning on ischemia-reperfusion injury in spontaneously hypertensive rats (SHR). Mol Cell Biochem 2007;296:45–51.
110. Arbeláez LFG, Pardo AC, Fantinelli JC, Mosca SM. Cyclosporine-A mimicked the ischemic pre-and postconditioning-mediated cardioprotection in hypertensive rats: Role of PKCε. Exp Mol Pathol 2016;100:266–75.
111. Penna C, Alloatti G, Crisafulli A. Mechanisms involved in cardioprotection induced by physical exercise. Antioxid Redox Signal 2020; 32:1115-34.
112. Borges JP, da Silva Verdoorn K. Cardiac ischemia/reperfusion injury: the beneficial effects of exercise. In: Exercise for Cardiovascular Disease Prevention and Treatment. Berlin: Springer, 2017; pp 155–179.
113. Diaz RJ, Wilson GJ. Selective blockade of AT1angiotensin II receptors abolishes ischemic preconditioning in isolated rabbit hearts. J Mol Cell Cardiol 1997;29:129-39.
114. Takeishi Y, Ping P, Bolli R, Kirkpatrick DL, Hoit BD, Walsh RA. Transgenic overexpression of constitutively active protein kinase C ε causes concentric cardiac hypertrophy. Circ Res 2000;86:1218–23.
115. Newton AC, Antal CE, Steinberg SF. Protein kinase C mechanisms that contribute to cardiac remodelling. Clin Sci 2016;130:1499–510.
116. Ping P, Takano H, Zhang J, Tang XL, Qiu Y, Li RC, et al. Isoform-selective activation of protein kinase C by nitric oxide in the heart of conscious rabbits: a signaling mechanism for both nitric oxide–induced and ischemia-induced preconditioning. Circ Res 1999;84:587–604.
117. Qiu Y, Ping P, Tang XL, Manchikalapudi S, Rizvi A, Zhang J, et al. Direct evidence that protein kinase C plays an essential role in the development of late preconditioning against myocardial stunning in conscious rabbits and that epsilon is the isoform involved. J Clin Invest 1998;101:2182–98.
118. Teng JC, Kay H, Chen Q, Adams JS, Grilli C, Guglielmello G, et al. Mechanisms related to the cardioprotective effects of protein kinase C epsilon (PKC ɛ) peptide activator or inhibitor in rat ischemia/reperfusion injury. Naunyn Schmiedebergs Arch Pharmacol 2008;378:1–15.
119. Wang G-Y, Zhou JJ, Shan J, Wong T-M. Protein kinase C-ε is a trigger of delayed cardioprotection against myocardial ischemia of κ-opioid receptor stimulation in rat ventricular myocytes. J Pharmacol Exp Ther 2001;299:603–10.
120. Wu S, Li HY, Wong TM. Cardioprotection of preconditioning by metabolic inhibition in the rat ventricular myocyte: involvement of κ-opioid receptor. Circ Res 1999;84:1388–95.
121. Otani H. Reactive oxygen species as mediators of signal transduction in ischemic preconditioning. Antioxid Redox Signal 2004;6:449-69.
122. Uchiyama Y, Otani H, Wakeno M, Okada T, Uchiyama T, Sumida T, et al. Role of mitochondrial KATP channels and protein kinase C in ischaemic preconditioning. Clin Exp Pharmacol Physiol 2003;30:426-36.
123. Bolli R, Dawn B, Tang XL, Qiu Y, Ping P, Xuan YT, et al. The nitric oxide hypothesis of late preconditioning. Basic Res Cardiol 1998;93:325-38.
124. Nakano A, Liu GS, Heusch G, Downey JM, Cohen MV. Exogenous nitric oxide can trigger a preconditioned state through a free radical mechanism, but endogenous nitric oxide is not a trigger of classical ischemic preconditioning. J Mol Cell Cardiol 2000;32:1159-67.
125. Tappia PS, Shah AK, Ramjiawan B, Dhalla NS. Modification of ischemia/reperfusion-induced alterations in subcellular organelles by ischemic preconditioning. Int J Mol Sci 2022;23:3425. doi: 10.3390/ijms23073425.
126. Hao Z, Pan SS, Shen YJ, Ge J. Exercise preconditioning-induced early and late phase of cardioprotection is associated with protein kinase C epsilon translocation. Circ J 2014;78:1636-45.
127. Malhotra A, Kang BPS, Hashmi S, Meggs LG. PKCε inhibits the hyperglycemia-induced apoptosis signal in adult rat ventricular myocytes. Mol Cell Biochem 2005;268:169-73.
128. Shizukuda Y, Reyland ME, Buttrick PM. Protein kinase C-δ modulates apoptosis induced by hyperglycemia in adult ventricular myocytes. Am J Physiol Heart Circ Physiol 2002;282:H1625–34.
129. Malhotra A, Begley R, Kang BP, Rana I, Liu J, Yang G, et al. PKC-ε-dependent survival signals in diabetic hearts. Am J Physiol Heart Circ Physiol 2005;289:H1343–50.
130. House SL, Melhorn SJ, Newman G, Doetschman T, Schultz Jel J. The protein kinase C pathway mediates cardioprotection induced by cardiac-specific overexpression of fibroblast growth factor-2. Am J Physiol Heart Circ Physiol 2007;293:H354–65.
131. Liao S, Bodmer JR, Azhar M, Newman G, Coffin JD, Doetschman T, et al. The influence of FGF2 high molecular weight (HMW) isoforms in the development of cardiac ischemia–reperfusion injury. J Mol Cell Cardiol 2010;48:1245–54.
132. Das A, Ockaili R, Salloum F, Kukreja RC. Protein kinase C plays an essential role in sildenafil-induced cardioprotection in rabbits. Am J Physiol Heart Circ Physiol 2004;286:H1455–60.
133. Otsu M, Hiles I, Gout I, Fry MJ, Ruiz-Larrea F, Panayotou G, et al. Characterization of two 85 kd proteins that associate with receptor tyrosine kinases, middle-T/pp60c-src complexes, and PI3-kinase. Cell 1991;65:91–104.
134. Skolnik EY, Margolis B, Mohammadi M, Lowenstein E, Fischer R, Drepps A, et al. Cloning of PI3 kinase-associated p85 utilizing a novel method for expression/cloning of target proteins for receptor tyrosine kinases. Cell 1991;65:83–90.
135. Vanhaesebroeck B, Stephens L, Hawkins P. PI3K signalling: the path to discovery and understanding. Nat Rev Mol Cell Biol 2012;13:195–203.
136. Miled N, Yan Y, Hon WC, Perisic O, Zvelebil M, Inbar Y, et al. Mechanism of two classes of cancer mutations in the phosphoinositide 3-kinase catalytic subunit. Science 2007;317:239–42.
137. Huang CH, Mandelker D, Schmidt-Kittler O, Samuels Y, Velculescu VE, Kinzler KW, et al. The structure of a human p110α/p85α complex elucidates the effects of oncogenic PI3Kα mutations. Science 2007;318:1744–8.
138. Walker EH, Pacold ME, Perisic O, Stephens L, Hawkins PT, Wymann MP, et al. Structural determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin, and staurosporine. Mol Cell 2000;6:909–19.
139. Patrucco E, Notte A, Barberis L, Selvetella G, Maffei A, Brancaccio M, et al. PI3Kγ modulates the cardiac response to chronic pressure overload by distinct kinase-dependent and-independent effects. Cell 2004;118:375–87.
140. Hua R, Adamczyk A, Robbins C, Ray G, Rose RA. Distinct patterns of constitutive phosphodiesterase activity in mouse sinoatrial node and atrial myocardium. PLoS One 2012:7:e 47652. doi: 10.1371/journal.pone.0047652.
141. Kolár F, Jezková J, Balková P, Breh J, Neckár J, Novák F, et al. Role of oxidative stress in PKC-δ upregulation and cardioprotection induced by chronic intermittent hypoxia. Am J Physiol Heart Circ Physiol 2007;92:H224–30.
142. Collier PN, Martinez-Botella G, Cornebise M, Cottrell KM, Doran JD, Griffith JP, et al. Structural basis for isoform selectivity in a class of benzothiazole inhibitors of phosphoinositide 3-kinase γ. J Med Chem 20015;58:517–21.
143. Durrant TN, Hers I. PI3K inhibitors in thrombosis and cardiovascular disease. Clin Transl Med 2020;9:1–21.
144. Perrino C, Naga Prasad SV, Patel M, Wolf MJ, Rockman HA. Targeted inhibition of β-adrenergic receptor kinase-1–associated phosphoinositide-3 kinase activity preserves β-adrenergic receptor signaling and prolongs survival in heart failure induced by calsequestrin overexpression. J Am Coll Cardiol 2005;45:1862–70.
145. Perrino C, Naga Prasad SV, Schroder JN, Hata JA, Milano C, Rockman HA. Restoration of β-adrenergic receptor signaling and contractile function in heart failure by disruption of the βARK1/phosphoinositide 3-kinase complex. Circulation 2005;111:2579–87.
146. Nienaber JJ, Tachibana H, Naga Prasad SV, Esposito G, Wu D, Mao L, et al. Inhibition of receptor-localized PI3K preserves cardiac β-adrenergic receptor function and ameliorates pressure overload heart failure. J Clin Invest 2003;112:1067–79.
147. Awad AE, Kandalam V, Chakrabarti S, Wang X, Penninger JM, Davidge ST, et al. Tumor necrosis factor induces matrix metalloproteinases in cardiomyocytes and cardiofibroblasts differentially via superoxide production in a PI3Kγ-dependent manner. Am J Physiol Cell Physiol 2010;298:C679–92.
148. Perrino C, Naga Prasad SV, Mao L, Noma T, Yan Z, Kim HS, et al. Intermittent pressure overload triggers hypertrophy-independent cardiac dysfunction and vascular rarefaction. J Clin Invest 2006;116:1547–60.
149. Luo J, McMullen JR, Sobkiw CL, Zhang L, Dorfman AL, Sherwood MC, et al. Class IA phosphoinositide 3-kinase regulates heart size and physiological cardiac hypertrophy. Mol Cell Biol 2005;25:9491–502.
150. Shioi T, Kang PM, Douglas PS, Hampe J, Yballe CM, Lawitts J, Cantley LC, et al. The conserved phosphoinositide 3‐kinase pathway determines heart size in mice. EMBO J 2000;19:2537–48.
151. Deschamps AM, Murphy E. Activation of a novel estrogen receptor, GPER, is cardioprotective in male and female rats. Am J Physiol Heart Circ Physiol 2009;297:H1806–13.
152. Bopassa JC, Eghbali M, Toro L, Stefani E. A novel estrogen receptor GPER inhibits mitochondria permeability transition pore opening and protects the heart against ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol 2010;298:H16–H23.
153. Chaudhary KR, Batchu SN, Das D, Suresh MR, Falck JR, et al. Role of B-type natriuretic peptide in epoxyeicosatrienoic acid-mediated improved post-ischaemic recovery of heart contractile function. Cardiovasc Res 2009;83:362–70.
154. Okumura H, Nagaya N, Itoh T, Okano I, Hino J, Mori K, et al. Adrenomedullin infusion attenuates myocardial ischemia/reperfusion injury through the phosphatidylinositol 3-kinase/Akt-dependent pathway. Circulation 2004;109:242–8.
155. Yin H, Chao L, Chao J. Adrenomedullin protects against myocardial apoptosis after ischemia/reperfusion through activation of Akt-GSK signaling. Hypertension 2004;43:109–16.
156. Pretorius L, Du XJ, Woodcock EA, Kiriazis H, Lin RC, Marasco S, et al. Reduced phosphoinositide 3-kinase (p110α) activation increases the susceptibility to atrial fibrillation. Am J Pathol 2009;175:998–1009.
157. Lu Z, Jiang YP, Wang W, Xu XH, Mathias RT, Entcheva E, et al. Loss of cardiac phosphoinositide 3-kinase p110α results in contractile dysfunction Circulation 2009;120:318-25.
158. McMullen JR, Amirahmadi F, Woodcock EA, Schinke-Braun M, Bouwman RD, Hewitt KA, et al. Protective effects of exercise and phosphoinositide 3-kinase (p110α) signaling in dilated and hypertrophic cardiomyopathy. Proc Natl Acad Sci 2007;104:612–7.
159. Curcio A, Noma T, Naga Prasad SV, Wolf MJ, Lemaire A, Perrino C, et al. Competitive displacement of phosphoinositide 3-kinase from β-adrenergic receptor kinase-1 improves postinfarction adverse myocardial remodeling. Am J Physiol Heart Circ Physiol 2006; 291:H1754-60.
160. Schindler JF, Monahan JB, Smith WG. p38 pathway kinases as anti-inflammatory drug targets. J Dent Res 2007;86:800–11.
161. Xu YJ, Saini HK, Zhang M, Elimban V, Dhalla NS. MAPK activation and apoptotic alterations in hearts subjected to calcium paradox are attenuated by taurine. Cardiovasc Res 72:163–74.
162. Wang Y, Huang S, Sah VP, Ross J Jr, Brown JH, Han J, et al. Cardiac muscle cell hypertrophy and apoptosis induced by distinct members of the p38 mitogen-activated protein kinase family. J Biol Chem 1998;273:2161–8.
163. See F, Thomas W, Way K, Tzanidis A, Kompa A, Lewis D, et al. p38 mitogen-activated protein kinase inhibition improves cardiac function and attenuates left ventricular remodeling following myocardial infarction in the rat. J Am Coll Cardiol 2004;44:1679-89.
164. Barancik M, Htun P, Strohm C, Kilian S, Schaper W. Inhibition of the cardiac p38-MAPK pathway by SB203580 delays ischemic cell death. J Cardiovasc Pharmacol 2000;35:474–83.
165. Nagarkatti DS, Ramadan IS. Role of p38 MAP kinase in myocardial stress. J Mol Cell Cardiol 1998;30:1651–64.
166. Martin JL, Avkiran M, Quinlan RA, Cohen P, Marber MS. Antiischemic effects of SB203580 are mediated through the inhibition of p38α mitogen-activated protein kinase: evidence from ectopic expression of an inhibition-resistant kinase. Circ Res 2001;89:750-2.
167. Otsu K, Yamashita N, Nishida K, Hirotani S, Yamaguchi O, Watanabe T, et al. Disruption of a single copy of the p38α MAP kinase gene leads to cardioprotection against ischemia–reperfusion. Biochem Biophys Res Commun 2003;302:56–60.
168. Fan L, Sawbridge D, George V, Teng L, Bailey A, Kitchen I, et al. Chronic cocaine-induced cardiac oxidative stress and mitogen-activated protein kinase activation: the role of Nox2 ocidase. J Pharmacol Exp Ther 2009;328:99-106.
169. Bao W, Behm DJ, Nerurkar SS, Ao Z, Bentley R, Mirabile RC, et al. Effects of p38 MAPK Inhibitor on angiotensin II-dependent hypertension, organ damage, and superoxide anion production. J Cardiovasc Pharmacol 2007;49:362–8.
170. Sato H, Tanaka T, Kasai K, Kita T, Tanaka N. Role of p38 mitogen-activated protein kinase on cardiac dysfunction after hemorrhagic shock in rats. Shock 2007;28:291–9.
171. Westermann D, Rutschow S, Van Linthout S, Linderer A, Bücker-Gärtner C, Sobirey M, et al. Inhibition of p38 mitogen-activated protein kinase attenuates left ventricular dysfunction by mediating pro-inflammatory cardiac cytokine levels in a mouse model of diabetes mellitus. Diabetologia 2006;49:2507–13.
172. Kyoi S, Otani H, Matsuhisa S, Akita Y, Tatsumi K, Enoki C, et al. Opposing effect of p38 MAP kinase and JNK inhibitors on the development of heart failure in the cardiomyopathic hamster. Cardiovasc Res 2006;69:888–98.
173. Li Z, Ma JY, Kerr I, Chakravarty S, Dugar S, Schreiner G, et al. Selective inhibition of p38α MAPK improves cardiac function and reduces myocardial apoptosis in rat model of myocardial injury. Am J Physiol Heart Circ Physiol 2006;291:H1972–7.
174. Malhotra A, Kang BP, Opawumi D, Belizaire W, Meggs LG. Molecular biology of protein kinase C signaling in cardiac myocytes. Mol Cell Biochem 2001;225:97–107.
175. Muslin AJ. MAPK signaling in cardiovascular health and disease: Molecular mechanisms and therapeutic targets. Clin Sci 2008;115:203-18.
176. Stefanovsky VY, Pellitier G, Hannan R, Gagonon Kugler T, Rothblum LI, Moss T. An immediate response of ribosomal transcription to growth factor stimulation is mediated by ERK phosphorylation of UBF. Mol Cell 2001;81:1063-73.
177. Heft MA, Harder BA, Eppenberger H. Schaub MC Signaling pathways in cardiac myocycte hypertrophy. J Mol Cell Cardiol 1997;29:2873-92.
178. Shao Q, Takeda N, Temsah R, Dhalla KS, Dhalla NS. Prevention of hemodynamic changes due to myocardial infarction by early treatment with imidapril. Cardioasc Pathol 1996;1:180-6.
179. Weinberg EO, Schoen FJ, George D, Kagaya Y, Douglas PS, Litwin SE, et al. Angiotensin converting enzyme inhibitors prolong survival and modifies the transition to heart failure in rats with pressure overload hypertrophy due to ascending aortic stenosis. Circulation 1994;90:1410-22.
180. Haq S, Choukroun G, Lim H, Tymitz KM, del Monte F, Gwathmey J, et al. Differential activation of signal transduction pathways in human hearts with hypertrophy versus advanced heart failure. Circulation 2001;103:670-7.
181. Yano M, Kim S, Izumi Y Yamanaka S, Iwao H. Differential activation of cardiac c-jun amino-terminal kinase and extracellular signal-regulated kinase in angiotensin II-mediated hypertension. Circ Res 1998;83:752-60.
182. Yoshida K, Yoshiyama M, Omura T, Nakamura Y, Kim S, Takeuchi K, et al. Activation of mitogen-activated protein kinases in the non-ishemic myocardium of an acute myocardial infarction in rats. Jpn Circ J 2001;65:808-14.
183. Knight R, Buxton D. Stimulation of c-jun kinase and mitogen-activated protein kinase by ishemia and reperfusion in the perfused rat heart. Biochem Biophys Res Commun 1996;218:83-8.
184. Behrends M, Schulz R, Post H, Alexandrov A, Belosjorow S, Michel MC, et al. Inconsistent relation of MAPK activation to infarct size reduction by ischemic preconditioning in pigs. Am J Physiol Heart Circ Physiol 2000;279:H1111-9.
185. Bogoyevitch MA, Gillespie-Brown J, Ketterman AJ, Fuller SJ, Ben-Levy R, Ashworth A, et al. Stimulation of the stress-activated mitogen-activated protein kinase subfamilies in perfused heart. p38/RK mitogen -activated protein kinases and c-jun N-terminal kinases are activated by ischemia/reperfusion. Circ Res 1996;79:162-73.
186. Yue TL, Wang C, Gu JL, Ma XL, Kumar S, Lee JC, et al. Inhibition of extracellular signal-regulated kinase enhances ischemia/reoxygenation-induced apoptosis in cultural cardiac myocyctes and exaggerates reperfusion injury in isolated perfused heart. Circ Res 2000;86:692-9.
187. Bueno OF, De Windt LJ, Tymitz KM, Witt SA, Kimball TR, Klevitsky R, et al. The MEKI-ERK½ signaling pathway promotes compensated cardiac hypertrophy in transgenic mice. EMBO J 2000;19:6341-50.
188. Xia, Z, Dickens M. Raingeaud J, Davis RJ, Greenberg ME, Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science 1995;270:1326-31.
189. Horiuchi M, Akishita M, Dzau VJ. Recent progress in angiotensin II type 2 receptor research in the cardiovascular system. Hypertension 1999;33:613-21.
- Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution License that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal.
- Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgement of its initial publication in this journal.
- Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work (See The Effect of Open Access).