Inducible and myocyte-specific inhibition of PKCalpha enhances cardiac contractility and protects against infarction-induced heart failure.
Mice null for the gene encoding protein kinase Calpha (Prkca), or mice treated with pharmacologic inhibitors of the PKCalpha/beta/gamma isoforms, show an augmentation in cardiac contractility that appears to be cardioprotective. However, it remains uncertain if PKCalpha itself functions in a myocyte autonomous manner to affect cardioprotection in vivo. Here we generated cardiac myocyte-specific transgenic mice using a tetracycline-inducible system to permit controlled expression of dominant negative PKCalpha in the heart. Consistent with the proposed function of PKCalpha, induction of dominant negative PKCalpha 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 after myocardial infarction 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 PKCalpha protects the adult heart from decompensation and dilated cardiomyopathy after infarction injury in association with a primary enhancement in contractility.
Hambleton
Michael
M
Division of Molecular Cardiovascular Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA.
York
Allen
A
Sargent
Michelle A
MA
Kaiser
Robert A
RA
Lorenz
John N
JN
Robbins
Jeffrey
J
Molkentin
Jeffery D
JD
D000818:Animals; D006332:Cardiomegaly / Q000201:enzymology / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D006333:Heart Failure / Q000201:enzymology / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000235:genetics; D009203:Myocardial Infarction / Q000150:complications / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology*; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D051571:Protein Kinase C-alpha / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D018754:Ventricular Dysfunction / Q000201:enzymology / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*
C496630:Prkca protein, mouse; D051571:Protein Kinase C-alpha