title: Inhibition of Ras-GTPase, but not tyrosine kinases or Ca2+/calmodulin-dependent protein kinase II, improves recovery of cardiac function in the globally ischemic heart.
abstract: The signaling pathways involved in ischemic heart disease are not well characterized. In this study, the roles of Ras-GTPase, tyrosine kinases (TKs) and Ca2+/calmodulin-dependent protein kinase II (CaMKII) in global ischemia and reperfusion (I/R) in a perfused rat heart model were investigated and compared to beneficial effects produced by preconditioning (PC). A 40 min episode of global ischemia followed by a 30 min reperfusion 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). Hearts from male Wistar rats pre-treated with the tyrosine kinase inhibitor, genistein (1 mg/kg/day for 6 days), or the CaMKII inhibitor, KN-93 (578 ng/min for 6 days), produced detrimental effects on recovery of cardiac function and coronary hemodynamics. In contrast, pre-treatment with Ras-GTPase inhibitor FPT III (232 ng/min for 6 days) significantly enhanced cardiac recovery in terms of left ventricular contractility and coronary vascular hemodynamics. Treatment with FPT III also significantly reduced expression of the sodium-hydrogen exchanger-1 (NHE-1) which was elevated during I/R as detected by Western blotting. These data suggest that TKs and CaMKII are involved in signaling pathways leading to recovery from cardiac ischemia, whereas activation of Ras-GTPase signaling pathways are critical in the development of cardiac dysfunction due to I/R.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Kuwait University, Safat, Kuwait. ibenter@hsc.kuniv.edu.kw
authors.forename: Ibrahim F
authors.initials: IF
authors.lastname: Benter
authors.forename: Jasbir S
authors.initials: JS
authors.lastname: Juggi
authors.forename: Islam
authors.initials: I
authors.lastname: Khan
authors.forename: Saghir
authors.initials: S
authors.lastname: Akhtar
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003326:Coronary Circulation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D066298:In Vitro Techniques; D007274:Injections, Intraperitoneal; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology; D017202:Myocardial Ischemia / Q000201:enzymology* / Q000503:physiopathology; D015425:Myocardial Reperfusion; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020127:Recovery of Function / Q000187:drug effects* / Q000502:physiology; D017725:Ventricular Pressure / Q000187:drug effects / Q000502:physiology
chemical_list: D004791:Enzyme Inhibitors; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase; D011505:Protein-Tyrosine Kinases; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases