Abstract
It is well established that brief episodes of ischemia/reperfusion (I/R) [preconditioning (PC)] protect the myocardium from the damage induced by subsequent more prolonged I/R. However, the signaling pathways activated during PC or I/R are not well characterized. In this study, the role of Ras-GTPase, tyrosine kinases (TKs), epidermal growth factor receptor (EGFR) and Ca2 +/calmodulin-dependent protein kinase II (CaMK II) in mediating PC in a perfused rat heart model was investigated. A 40-min episode of global ischemia in perfused rat hearts produced significantly impaired cardiac function, measured as left ventricular developed pressure (Pmax) and left ventricular end-diastolic pressure (LVEDP), and impaired coronary hemodynamics, measured as coronary flow (CF) and coronary vascular resistance (CVR). PC significantly enhanced cardiac recovery after I/R. Combination of PC and FPT III (Ras-GTPase inhibitor FPT III; 232 ng/min for 6 days) treatment did not produce any additive benefits as compared to PC alone. In contrast, PC-induced improvements in cardiac function after I/R were significantly attenuated by pretreatment with genistein (1mg/kg/day for 6 days), a broad-spectrum inhibitor of TKs, or AG1478 (1mg/kg/day for 6 days), a specific inhibitor of EGFR tyrosine kinase or KN-93 (578 ng/min for 6 days), a CaMK II inhibitor, before PC. These observations suggest that PC and FPT III pretreatment may produce cardioprotection via similar mechanisms. Present results also indicate that activation of TKs and specifically activation of EGFR-mediated TKs and CaMK II-mediated regulation of calcium homeostasis are part of the PC mechanisms that improve recovery after I/R. (Mol Cell Biochem 268: 175–183, 2005)
Similar content being viewed by others
References
Abe J, Berk BC: Reactive oxygen species as mediators of signal transduction in cardiovascular disease. Trends Cardiovasc Med 8: 59–64, 1998
Jennings RB, Reimer KA: The cell biology of acute myocardial ischemia. Annu Rev Med 42: 225–246, 1991
Takeishi Y, Abe J, Lee J, Kawakatsu H, Walsh RA, Berk BC: Differential regulation of p90 ribosomal S6 kinase and big mitogen-activated protein kinase1 by ischemia/reperfusion and oxidative stress in perfused guinea pig hearts. Circ Res 85: 1164–1172, 1999
Cohen MV, Yang X, Liu GS, Heusch G, Downey JM: Acetylcholine, bradykinin, opioids, and phenylephrine, but not adenosine, trigger preconditioning by generation free radicals and opening mitochondrial KATP channels. Circ Res 89: 273–278, 2001
Cohen MV, Baines CP, Downey JM: Ischemic preconditioning: From adenosine receptor to KATP channel. Annu Rev Physiol 62: 79–109, 2000
Yellon DM, Downey JM: Preconditioning the myocardium: From cellular physiology to clinical cardiology. Physiol Rev 83: 1113–1151, 2003
Benter IF, Juggi JS, Khan I, Akhtar S: Inhibition of Ras-GTPase, but not tyrosine kinases or Ca/calmodulin-dependent protein kinase II, improves recovery of cardiac function in the globally ischemic heart. Mol Cell Biochem 259: 35–42, 2004
Benter IF, Juggi JS, Akhtar S: Role of Ras-GTPase and calcium/calmodulin-dependent protein kinase II, in the signal transduction mechanisms involved in hyperthermic preconditioning. In: N.S. Dhalla, H. Rupp, A. Angel and GN Pierce (eds). Pathophysiology of Cardiovascular Disease, Kluwer Academic Publishers, Boston, 2004, pp 101–107
Muthalif MM, Benter IF, Karzoun N, Fatima S, Harper J, Uddin MR, Malik KU: 20-Hydroxyeicosatetraenoic acid mediates calcium/calmodulin-dependent protein kinase II-induced mitogen-activated protein kinase activation in vascular smooth muscle cellls. Proc Natl Acad Sci USA 95: 12701–12706, 1998
Muthalif MM, Karzoun NA, Gaber L, Benter IF, Parmentier JH, Manne V, Malik KU: Angiotensin II-induced hypertension: Contribution of Ras GTPase/Mitogen-activated protein kinase and cytochrome P450 metabolites. Hypertension 35: 457–463, 2000
Muthalif MM, Benter IF, Malik KU: Contribution of Ras GTPase/MAP Kinase and Cytochrome P-450 Metabolites to Deoxycorticosterone-salt-induced Hypertension. Hypertension, 35 (Part2): 457–463, 2000
Deodato B, Altavilla D, Squadrito G, Campo GM, Arlotta M, Minutoli L, Saitta A, Cucinotta D, Calapai G, Caputi AP, Miano M, Squadrito F: Cardioprotection by the phytoestrogen genistein in experimental myocardial ischaemia-reperfusion injury. Br J Pharmacol 128: 1683–1690, 1999
Abe J, Okuda M, Huang Q, Yoshizumi M, Berk BC Reactive oxygen species activate p90 ribosomal S6 kinase via Fyn and Ras. J. Biol Chem 275(3):1739–1748, 2000.
Xiao X-H, Allen DG: Activity of the Na/H exchanger is critical to reperfusion damage and preconditioning in the isolated rat heart. Cardiovasc Res 48: 244–253, 2000
Avkiran M, Gross G, Karmazyn M, Klein H, Murphy E, Ytrehus K: Na+/H+ exchange in ischemia, reperfusion and preconditioning. Cardiovasc Res 50(1): 162–166, 2001
Avkiran M, Marber MS: Na(+)/H(+) exchange inhibitors for cardioprotective therapy: Progress, problems and prospects. J Am Cell Cardiol 39(5): 747–53, 2002
Quan H, Margot C LaPointe: Interleukin-1β Regulation of the human brain natriuretic peptide promoter involves Ras-, Rac-, and p38 Kinase-dependent pathways in cardiac myocytes. Hypertension 33(Part II): 283–289,1999
Bari M, Ken S, George Bou-Gharios, Jonathan R, Beauchamp, Ryszard T, Smolenski, Terence A, Partridge, Magdi H. Yacoub: Transplantation of skeletal myoblasts secreting an IL-1 inhibitor modulates adverse remodeling in infracted murine myocardium. Proc Natl Acad Sci USA 4216–4221, 2004
Benjamin JP, Leonid LR, Alden H, Harken, Charles AD: Inhibition of caspase 1 reduces human myocardial ischemic dysfunction via inhibition of IL-18 and IL-1β. Proc Natl Acad Sci USA 98: 2871–2976, 2001
Chen HQ, Tannous M, Veluthakal R, Amin R, Kowluru A: Novel roles for palmitoylation of Ras in IL-1 beta-induced nitric oxide release and caspase 3 activation in insulin-secreting beta cells. Biochem Pharmacol 66(9): 1681–94, 2003
Takahashi M, Mutoh M, ShojiY, Kamanaka Y, Naka M, Maruyama T, Sugimura T, Wakabayashi K: Transfection of K-rasAsp12 cDNA markedly elevates IL-1beta-and lipopolysaccharide-mediated inducible nitric oxide synthase expression in rat intestinal epithelial cells. Oncogene 22(48): 7667–7676, 2003
Zhong C, Zhou Y, Liu H: Nuclear factor kappaB and anesthetic preconditioning during myocardial ischemia-reperfusion. Anesthesiology 100(3): 540–546, 2004
Serafin A, Rosello-Catafau J, Prats N, Gelpi E, Rodes J, Peralta C: Ischemic preconditioning affects interleukin release in fatty livers of rats undergoing ischemia/reperfusion. Hepatology 39(3): 688–698, 2004
Zenya N, Muhammad A, Yuhichi S: Pathogenesis and Protection of Ischemia and Reperfusion injury in Myocardium. J Nippon Med Sch 70(5): 384–392, 2003
Yatani A, Okabe K, Polakis P, Halenbeck R, McCormick F, Brown AM: ras p21 and GAP inhibit coupling of muscarinic receptors to atrial K+ channels. Cell 61: 769–776, 1990
Atsuko Y, Lawrence AQ, Arthur MB, Gary MB: Rap 1A antagonizes the ability of Ras and Ras-Gap to inhibit Muscarinic K+ channels. J Biol Chem 266(33): 22222–22226, 1990
George A, Martin, Atsuko Y, Robin C, Leah C, Paul P, Arthur MB, Frank M: GAP Domains responsible for Ras p21-dependent inhibition of muscarinic atria K+ channel currents. Science 255: 192–194, 1992
Ping P, Murphy E: Role of p38 mitogen-activated protein kinases in preconditioning. A detrimental factor or a protective kinase? Circ Res 86: 921–922, 2000
Krieg T, Cui L, Qin Q, Cohen MV, Downey JM: Mitochondrial ROS generation following acetylcholine-induced EGF receptor transactivation requires metalloproteinase cleavage of proHB-EGF. J Mol Cell Cardiol 36(3): 435–443, 2004
Ichikawa Y, Miura T, Nakano A, Miki T, Nakamura Y, Tsuchihashi K, Shimamoto K: The role of ADAM protease in the tyrosine kinase-mediated trigger mechanism of ischemic preconditioning. Cardiovasc Res 62(1): 167–175, 2004
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 278: H1791–H1798, 2000
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Benter, I.F., Juggi, J.S., Khan, I. et al. 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 268, 175–183 (2005). https://doi.org/10.1007/s11010-005-3895-1
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/s11010-005-3895-1