title: Interruption of signal transduction between G protein and PKC-epsilon underlies the impaired myocardial response to ischemic preconditioning in postinfarct remodeled hearts.
abstract: 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.
authors.affiliation: Second Department of Internal Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Miki
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Miura
authors.forename: Masaya
authors.initials: M
authors.lastname: Tanno
authors.forename: Jun
authors.initials: J
authors.lastname: Sakamoto
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kuno
authors.forename: Satoshi
authors.initials: S
authors.lastname: Genda
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Matsumoto
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Ichikawa
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Shimamoto
mesh_terms: D000241:Adenosine / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers; D000818:Animals; D003600:Cytosol / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000187:drug effects / Q000378:metabolism*; D066298:In Vitro Techniques; D019157:Ischemic Preconditioning, Myocardial / Q000009:adverse effects*; D008297:Male; D009203:Myocardial Infarction / Q000378:metabolism* / Q000401:mortality / Q000503:physiopathology; D015425:Myocardial Reperfusion; D011493:Protein Kinase C / Q000187:drug effects / Q000378:metabolism*; D051744:Protein Kinase C-epsilon; D021381:Protein Transport; D011817:Rabbits; D018047:Receptors, Purinergic P1 / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction; D013777:Tetrazoles / Q000494:pharmacology; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D000068756:Valsartan; D020257:Ventricular Remodeling / Q000502:physiology*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D018047:Receptors, Purinergic P1; D013777:Tetrazoles; D000068756:Valsartan; D011493:Protein Kinase C; D051744:Protein Kinase C-epsilon; D019204:GTP-Binding Proteins; D014633:Valine; D000241:Adenosine