| 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. | |
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MedLine Citation:
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PMID: 15124905 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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:
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Ibrahim F Benter; Jasbir S Juggi; Islam Khan; Saghir Akhtar |
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Publication Detail:
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Type: In Vitro; Journal Article |
Journal Detail:
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Title: Molecular and cellular biochemistry Volume: 259 ISSN: 0300-8177 ISO Abbreviation: Mol. Cell. Biochem. Publication Date: 2004 Apr |
Date Detail:
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Created Date: 2004-05-04 Completed Date: 2005-01-25 Revised Date: 2009-11-19 |
Medline Journal Info:
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Nlm Unique ID: 0364456 Medline TA: Mol Cell Biochem Country: Netherlands |
Other Details:
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Languages: eng Pagination: 35-42 Citation Subset: IM |
Affiliation:
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Department of Pharmacology, Faculty of Medicine, Kuwait University, Safat, Kuwait. ibenter@hsc.kuniv.edu.kw |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Alkyl and Aryl Transferases
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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:
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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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