Protein Kinase Cα, but Not PKCβ or PKCγ, Regulates Contractility and Heart Failure Susceptibility Implications for Ruboxistaurin as a Novel Therapeutic Approach

Protein kinase (PK)C alpha, PKC beta, and PKC gamma comprise the conventional PKC isoform subfamily, which is thought to regulate cardiac disease responsiveness. Indeed, mice lacking the gene for PKC alpha 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 antagonizes failure, although the isoform responsible for these effects is unknown. Here, we investigated mice lacking PKC alpha, PKC beta, and PKC gamma for effects on cardiac contractility and heart failure susceptibility. PKC alpha(-/-) mice, but not PKC beta gamma(-/-) mice, showed increased cardiac contractility, myocyte cellular contractility, Ca2+ transients, and sarcoplasmic reticulum Ca2+ load. PKC alpha(-/-) mice were less susceptible to heart failure following long-term pressure-overload stimulation or 4 weeks after myocardial infarction injury, whereas PKC beta gamma(-/-) mice showed more severe failure. Infusion of ruboxistaurin (LY333531), an orally available PKC alpha/beta/gamma inhibitor, increased cardiac contractility in wild-type and PKC beta gamma(-/-) mice, but not in PKC alpha(-/-) mice. More importantly, ruboxistaurin prevented death in wild-type 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 PKC beta gamma(-/-) mice subjected to pressure overload, resulting in less death and heart failure, implicating PKC alpha as the primary target of this drug in mitigating heart disease. As an aside, PKC alpha beta gamma triple-null mice showed no defect in cardiac hypertrophy following pressure-overload stimulation. In conclusion, PKC alpha functions distinctly from PKC beta and PKC gamma 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. (Circ Res. 2009;105:194-200.)