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.
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Authors | Ibrahim F Benter, Jasbir S Juggi, Islam Khan, Saghir Akhtar |
Journal | Molecular and cellular biochemistry
(Mol Cell Biochem)
Vol. 259
Issue 1-2
Pg. 35-42
(Apr 2004)
ISSN: 0300-8177 [Print] Netherlands |
PMID | 15124905
(Publication Type: Journal Article)
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Chemical References |
- Enzyme Inhibitors
- Alkyl and Aryl Transferases
- p21(ras) farnesyl-protein transferase
- Protein-Tyrosine Kinases
- Calcium-Calmodulin-Dependent Protein Kinase Type 2
- Calcium-Calmodulin-Dependent Protein Kinases
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Topics |
- Alkyl and Aryl Transferases
(antagonists & inhibitors, metabolism)
- Animals
- Calcium-Calmodulin-Dependent Protein Kinase Type 2
- Calcium-Calmodulin-Dependent Protein Kinases
(antagonists & inhibitors, metabolism)
- Coronary Circulation
(drug effects, physiology)
- Enzyme Inhibitors
(administration & dosage)
- In Vitro Techniques
- Injections, Intraperitoneal
- Ischemic Preconditioning, Myocardial
- Male
- Myocardial Contraction
(drug effects, physiology)
- Myocardial Ischemia
(enzymology, physiopathology)
- Myocardial Reperfusion
- Myocardium
(enzymology, pathology)
- Protein-Tyrosine Kinases
(antagonists & inhibitors, metabolism)
- Rats
- Rats, Wistar
- Recovery of Function
(drug effects, physiology)
- Ventricular Pressure
(drug effects, physiology)
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