Protein kinase C is involved in resistance to myocardial infarction induced by heat stress.
Heat stress (HS) is known to protect against mechanical dysfunction and myocardial necrosis in myocardial ischemia-reperfusion models both in vivo and in vitro. However, the mechanisms involved in this form of cardioprotection remain unclear. Protein kinase C (PKC) and tyrosine kinase activation have both been shown to be involved in the delayed phase of protection following ischemic preconditioning, a phenomenon which appears to be analogous to HS-induced protection. Therefore, we investigated the role of PKC and tyrosine kinase in HS-induced resistance to myocardial infarction, in the isolated rat heart. The selective inhibitors chelerythrine (Che) and genistein (Gen) were used to inhibit PKC and tyrosine kinase, respectively. Rats were treated with Che (5 mg/kg, i.p.) or Gen (5 mg/kg, i.p.) or vehicle before they were either heat stressed (42 degrees C for 15 min) or sham anesthetized. Twenty-four h later their hearts were isolated, retrogradely perfused, and subjected to 35-min occlusion of the left coronary artery followed by 120-min of reperfusion. Infarct-to-risk ratio was significantly reduced in HS (19.9+/-1.1%) compared to sham (43.1+/-1.1%) hearts. This reduction in infarct size was abolished in chelerythrine-treated groups (43.8+/-1.9% in HS+Che v 44.9+/-2.0% in sham+Che), but was conserved in genistein-treated groups (17.7+/-0.9% in HS+Gen v 36.4+/-2.8% in sham+Gen). In order to confirm that genistein at this dose was effectively inhibiting tyrosine kinase activity, we observed the ability of the agent to prevent the hypoglycemic responses to insulin in a separate group of anesthetised rats receiving an i.v. insulin infusion. Western blot analysis of the myocardial hsp72 showed a HS-induced increase of this protein, which was modified by neither the PKC inhibitor, chelerythrine, nor the tyrosine kinase inhibitor, genistein. We conclude that the activation of PKC, but not of tyrosine kinase, appears to play a role in the functional cardioprotection associated with the heat stress response. Although protection appears to be dissociated from induction of hsp72, further work is required to explore the importance of hsp72 phosphorylation to cytoprotective activity of the protein.
Joyeux
M
M
The Hatter Institute for Cardiovascular Studies, University College London Hospitals & Medical School, London, UK.
Baxter
G F
GF
Thomas
D L
DL
Ribuot
C
C
Yellon
D M
DM
D000470:Alkaloids; D000818:Animals; D053119:Benzophenanthridines; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019833:Genistein / Q000494:pharmacology; D050884:HSP72 Heat-Shock Proteins; D006321:Heart / Q000187:drug effects; D018882:Heat Stress Disorders / Q000201:enzymology*; D006360:Heat-Shock Proteins / Q000378:metabolism; D006439:Hemodynamics; D007328:Insulin / Q000494:pharmacology; D008297:Male; D009203:Myocardial Infarction / Q000201:enzymology*; D009206:Myocardium / Q000201:enzymology; D010617:Phenanthridines / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014693:Ventricular Fibrillation
D000470:Alkaloids; D053119:Benzophenanthridines; D004791:Enzyme Inhibitors; D050884:HSP72 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D007328:Insulin; D010617:Phenanthridines; D019833:Genistein; C016299:chelerythrine; D011505:Protein-Tyrosine Kinases; D011493:Protein Kinase C