PKCα but not PKCβ or PKCγ regulates contractility and heart failure susceptibility: Implications for ruboxistaurin as a novel therapeutic approach

摘要

Protein kinase Cα (PKCα), PKCβ, and PKCγ comprise the conventional PKC isoform subfamily, which is thought to regulate cardiac disease responsiveness. Indeed, mice lacking the gene for PKCα show enhanced cardiac contractility and reduced susceptibility to heart failure. Recent data also suggest that inhibition of conventional PKC isoforms with Ro-32-0432 or Ro-31-8220 enhances heart function and antagonize failure, although the isoform responsible for these effects is unknown. Here we investigated mice lacking PKCα, PKCβ and PKCγ for effects on cardiac contractility and heart failure susceptibility. PKCα^−/− mice, but not PKCβγ^−/−, showed increased cardiac contractility, myocyte cellular contractility, Ca²⁺ transients, and sarcoplasmic reticulum Ca²⁺ load. PKCα^−/− mice were less susceptible to heart failure following long-term pressure overload stimulation or 4 weeks after myocardial infarction injury, while PKCβγ^−/− mice showed more severe failure. Infusion of ruboxistaurin (), an orally available PKCα/β/γ inhibitor, increased cardiac contractility in wildtype and PKCβγ^−/− mice, but not in PKCα^−/− mice. More importantly, ruboxistaurin prevented death in wildtype mice throughout 10 weeks of pressure overload stimulation, reduced ventricular dilation, enhanced ventricular performance, reduced fibrosis, and reduced pulmonary edema comparable to or better than metoprolol treatment. Ruboxistaurin was also administered to PKCβγ^−/− mice subjected to pressure overload, resulting in less death and heart failure, implicating PKCα as the primary target of this drug in mitigating heart disease. As an aside, PKCαβγ triple null mice showed no defect in cardiac hypertrophy following pressure overload stimulation. In conclusion, PKCα functions distinct from PKCβ and PKCγ in regulating cardiac contractility and heart failure, and broad acting PKC inhibitors such as ruboxistaurin, could represent a novel therapeutic approach in treating human heart failure.