title: Signal transduction mechanisms involved in cardiac preconditioning: role of Ras-GTPase, Ca2+/calmodulin-dependent protein kinase II and epidermal growth factor receptor.
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 IR. 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 IR.
authors.affiliation: Department of Pharmacology & Toxicology, Faculty of Medicine, Kuwait University, Safat, Kuwait. ibenter@hsc.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: Mariam H M
authors.initials: MH
authors.lastname: Yousif
authors.forename: Halit
authors.initials: H
authors.lastname: Canatan
authors.forename: Saghir
authors.initials: S
authors.lastname: Akhtar
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology*; D009924:Organ Culture Techniques; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects*; D020663:ras Guanine Nucleotide Exchange Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D020663:ras Guanine Nucleotide Exchange Factors; D066246:ErbB Receptors; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002118:Calcium
references.citation: Proc Natl Acad Sci U S A. 2001 Feb 27;98(5):2871-6
references.pmid: 11226333
references.citation: J Biol Chem. 1991 Nov 25;266(33):22222-6
references.pmid: 1939245
references.citation: Annu Rev Med. 1991;42:225-46
references.pmid: 2035969
references.citation: Hepatology. 2004 Mar;39(3):688-98
references.pmid: 14999687
references.citation: Biochem Pharmacol. 2003 Nov 1;66(9):1681-94
references.pmid: 14563479
references.citation: Oncogene. 2003 Oct 23;22(48):7667-76
references.pmid: 14576830
references.citation: J Nippon Med Sch. 2003 Oct;70(5):384-92
references.pmid: 14578938
references.citation: J Biol Chem. 2000 Jan 21;275(3):1739-48
references.pmid: 10636870
references.citation: Cardiovasc Res. 2000 Nov;48(2):244-53
references.pmid: 11054471
references.citation: Circ Res. 2000 May 12;86(9):921-2
references.pmid: 10807861
references.citation: Physiol Rev. 2003 Oct;83(4):1113-51
references.pmid: 14506302
references.citation: Annu Rev Physiol. 2000;62:79-109
references.pmid: 10845085
references.citation: Circ Res. 2001 Aug 3;89(3):273-8
references.pmid: 11485978
references.citation: Hypertension. 2000 Jan;35(1 Pt 2):457-63
references.pmid: 10642341
references.citation: Hypertension. 1999 Jan;33(1 Pt 2):283-9
references.pmid: 9931118
references.citation: Am J Physiol Heart Circ Physiol. 2000 Jun;278(6):H1791-8
references.pmid: 10843874
references.citation: J Mol Cell Cardiol. 2004 Mar;36(3):435-43
references.pmid: 15010282
references.citation: Mol Cell Biochem. 2004 Apr;259(1-2):35-42
references.pmid: 15124905
references.citation: J Am Coll Cardiol. 2002 Mar 6;39(5):747-53
references.pmid: 11869836
references.citation: Trends Cardiovasc Med. 1998 Feb;8(2):59-64
references.pmid: 21235913
references.citation: Br J Pharmacol. 1999 Dec;128(8):1683-90
references.pmid: 10588923
references.citation: Circ Res. 1999 Dec 3-17;85(12):1164-72
references.pmid: 10590243
references.citation: Cell. 1990 Jun 1;61(5):769-76
references.pmid: 2188736
references.citation: Proc Natl Acad Sci U S A. 1998 Oct 13;95(21):12701-6
references.pmid: 9770549
references.citation: Cardiovasc Res. 2001 Apr;50(1):162-6
references.pmid: 11345942
references.citation: Proc Natl Acad Sci U S A. 2004 Mar 23;101(12):4216-21
references.pmid: 15020774
references.citation: Science. 1992 Jan 10;255(5041):192-4
references.pmid: 1553544
references.citation: Cardiovasc Res. 2004 Apr 1;62(1):167-75
references.pmid: 15023563
references.citation: Anesthesiology. 2004 Mar;100(3):540-6
references.pmid: 15108966