Responses of cardiac protein kinase C isoforms to distinct pathological stimuli are differentially regulated

Currently at least II protein kinase C (PKC) isoforms have been identified and may play different roles in cell signaling pathways leading to changes in cardiac contractility, the hypertrophic response, and tolerance to myoca rdial ischemia, The purpose of the present study was to test the hypothesis that responses of individual PKC isoforms to distinct pathological stimuli were differentially regulated in the adult guinea pig heart. Isolated hear ts were perfused by the Langendorff method and were exposed to ischemia, hy poxia, H2O2, or angiotensin II. Hypoxia and ischemia induced translocation of PKC isoforms alpha, beta(2), gamma, and zeta, and H2O2 translocated PKC isoforms alpha, beta(2), and zeta. Angiotensin II produced translocation of alpha, beta(2), epsilon, gamma, and zeta isoforms. Inhibition of phospholi pase C with tricyclodecan-9-yl-xanthogenate (D609) blocked hypoxia-induced (alpha, beta(2), and zeta) and angiotensin II-induced (alpha, beta(2), gamm a, and zeta) translocation of PKC isoforms, Inhibition of tyrosine kinase w ith genistein blocked translocation of PKC isoforms by hypoxia (beta(2) and zeta) and by angiotensin II (beta(2)). By contrast, neither D609 nor genis tein blocked H2O2-induced translocation of any PKC isoform. We conclude tha t hypoxia-induced activation of PKC isoforms is mediated through pathways i nvolving phospholipase C and tyrosine kinase, but oxidative stress may acti vate PKC isoforms independently of G alpha q-phospholipase C coupling and t yrosine kinase signaling. Because oxidative stress may directly activate PK C, and PKC activation appears to be involved in human heart failure, select ive inhibition of the PKC isoforms may provide a novel therapeutic strategy for the prevention and treatment of this pathological process.