Document Detail


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.
MedLine Citation:
PMID:  15124905     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Ibrahim F Benter; Jasbir S Juggi; Islam Khan; Saghir Akhtar
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Publication Detail:
Type:  In Vitro; Journal Article    
Journal Detail:
Title:  Molecular and cellular biochemistry     Volume:  259     ISSN:  0300-8177     ISO Abbreviation:  Mol. Cell. Biochem.     Publication Date:  2004 Apr 
Date Detail:
Created Date:  2004-05-04     Completed Date:  2005-01-25     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  0364456     Medline TA:  Mol Cell Biochem     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  35-42     Citation Subset:  IM    
Affiliation:
Department of Pharmacology, Faculty of Medicine, Kuwait University, Safat, Kuwait. ibenter@hsc.kuniv.edu.kw
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MeSH Terms
Descriptor/Qualifier:
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*
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
Chemical
Reg. No./Substance:
0/Enzyme Inhibitors; EC 2.5.-/Alkyl and Aryl Transferases; EC 2.5.1.-/p21(ras) farnesyl-protein transferase; EC 2.7.10.1/Protein-Tyrosine Kinases; EC 2.7.11.17/Calcium-Calmodulin-Dependent Protein Kinase Type 2; EC 2.7.11.17/Calcium-Calmodulin-Dependent Protein Kinases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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