Document Detail

Interruption of signal transduction between G protein and PKC-epsilon underlies the impaired myocardial response to ischemic preconditioning in postinfarct remodeled hearts.
MedLine Citation:
PMID:  12841647     Owner:  NLM     Status:  MEDLINE    
We have recently shown that the protective mechanism of ischemic preconditioning (PC) is impaired in the myocardium that survived infarction and underwent postinfarct ventricular remodeling. In this study, we examined the hypothesis that failure of PC to activate PKC-epsilon underlies the refractoriness of the remodeling heart to PC. Circumflex coronary arteries were ligated in rabbits to induce infarction and subsequent ventricular remodeling, and only sham operations were performed in controls. Hearts were isolated before (i.e. 4 days later) or after (i.e. 2 weeks later) remodeling of the left ventricle and used for isolated buffer-perfused heart experiments. Myocardial infarction was induced in isolated hearts by 30 min global ischemia/2 h reperfusion, and its size was measured by tetrazolium staining. Using separate groups of hearts, tissue biopsies were taken before and after PC, and PKC translocation was assessed by Western blotting. Areas infarcted in vivo by coronary ligation (CL) were excluded from subsequent infarct size/PKC analyses. In the hearts 4 days after CL, PC with 2 cycles of 5 min ischemia/5 min reperfusion induced PKC-epsilon translocation from cytosol to particulate fractions and limited infarct size to 40% of control value. In the hearts remodeled 2 weeks after CL, PC failed to induce PKC-epsilon translocation and infarct size limitation. In this group, PKC activity and hemodynamic responses to adenosine were similar to those in sham-operated controls. When remodeling after CL was prevented by valsartan infusion (10 mg/kg/day), an angiotensin II type 1 (AT1) receptor blocker, PC could induce both infarct limitation and PKC-epsilon translocation. The present results suggest that persistent activation of AT1 receptors during remodeling disturbed the PC signaling between G proteins and PKC-epsilon, which underlies the refractoriness of the remodeled myocardium to PC.
Takayuki Miki; Tetsuji Miura; Masaya Tanno; Jun Sakamoto; Atsushi Kuno; Satoshi Genda; Tomoaki Matsumoto; Yoshihiko Ichikawa; Kazuaki Shimamoto
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Molecular and cellular biochemistry     Volume:  247     ISSN:  0300-8177     ISO Abbreviation:  Mol. Cell. Biochem.     Publication Date:  2003 May 
Date Detail:
Created Date:  2003-07-04     Completed Date:  2004-04-15     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  0364456     Medline TA:  Mol Cell Biochem     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  185-93     Citation Subset:  IM    
Second Department of Internal Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.
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MeSH Terms
Adenosine / pharmacology
Angiotensin II Type 1 Receptor Blockers
Cytosol / metabolism
GTP-Binding Proteins / drug effects,  metabolism*
Ischemic Preconditioning, Myocardial / adverse effects*
Myocardial Infarction / metabolism*,  mortality,  physiopathology
Myocardial Reperfusion
Protein Kinase C / drug effects,  metabolism*
Protein Kinase C-epsilon
Protein Transport
Receptors, Purinergic P1 / drug effects,  metabolism
Signal Transduction
Tetrazoles / pharmacology
Valine / analogs & derivatives,  pharmacology
Ventricular Remodeling / physiology*
Reg. No./Substance:
0/Angiotensin II Type 1 Receptor Blockers; 0/Receptors, Purinergic P1; 0/Tetrazoles; 137862-53-4/valsartan; 58-61-7/Adenosine; 7004-03-7/Valine; EC Kinase C; EC Kinase C-epsilon; EC 3.6.1.-/GTP-Binding Proteins

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