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Articles by J. N Lorenz
Total Records ( 2 ) for J. N Lorenz
  Q Liu , X Chen , S. M MacDonnell , E. G Kranias , J. N Lorenz , M Leitges , S. R Houser and J. D. Molkentin

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

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