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Am J Physiol Heart Circ Physiol (October 5, 2007). doi:10.1152/ajpheart.00486.2007
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Submitted on April 23, 2007
Accepted on October 1, 2007

Inducible and myocyte-specific inhibition of PKC{alpha} enhances cardiac contractility and protects against infarction-induced heart failure

Michael Hambleton1, Allen York2, Michelle A Sargent2, Robert A Kaiser1, John N. Lorenz3, Jeffrey Robbins1, and Jeffery D Molkentin1*

1 Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States
2 Pediatrics, Cincinnati Children's Hospital Medical Center, cincinnati, Ohio, United States
3 Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, Ohio, United States

* To whom correspondence should be addressed. E-mail: Molkj0{at}chmcc.org.

Mice null for the gene encoding protein kinase C{alpha} (Prkca), or mice treated with pharmacologic inhibitors of the PKC{alpha}/{beta}/{gamma} isoforms, show an augmentation in cardiac contractility that appears to be cardioprotective. However, it remains uncertain if PKC{alpha} itself functions in a myocyte autonomous manner to effect cardioprotection in vivo. Here we generated cardiac myocyte-specific transgenic mice using a tetracycline-inducible system to permit controlled expression of dominant negative (dn) PKC{alpha} in the heart. Consistent with the proposed function of PKC{alpha}, induction of dnPKC{alpha}expression in the adult heart enhanced baseline cardiac contractility. This increase in cardiac contractility was associated with a partial protection from long-term decompensation and secondary dilated cardiomyopathy following myocardial infarction (MI) injury. Similarly, Prkca null mice were also partially protected from infarction-induced heart failure, although the area of infarction injury was identical to controls. Thus, myocyte autonomous inhibition of PKC{alpha} protects the adult heart from decompensation and dilated cardiomyopathy following infarction injury, in association with a primary enhancement in contractility.




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