Published online before print September 12, 2002, doi: 10.1161/01.RES.0000037091.64492.69
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© 2002 American Heart Association, Inc.
Integrative Physiology |
Ischemic Protection and Myofibrillar Cardiomyopathy
Dose-Dependent Effects of In Vivo 
PKC Inhibition
From the Department of Internal Medicine, Division of Cardiology (H.S.H., M.G.Y., T.T., Y.M., T.J.B., G.W.D.), University of Cincinnati Medical Center, Cincinnati, Ohio; and the Division of Cardiovascular Molecular Biology (H.O., J.R.), the Children’s Hospital Research Foundation, Cincinnati, Ohio.
Correspondence to G.W. Dorn II, Division of Cardiology, University of Cincinnati Medical Center, 231 Albert B. Sabin Way, Cincinnati, Ohio 45267-0542. E-mail dorngw{at}ucmail.uc.edu
To delineate the in vivo cardiac functions requiring normal 
protein kinase C (PKC) activity, we pursued loss-of-function through transgenic expression of a PKC-specific translocation inhibitor protein fragment, V1, in mouse hearts. Initial results using the mouse 
-myosin heavy chain (MHC) promoter resulted in a lethal heart failure phenotype. Viable V1 mice were therefore obtained using novel attenuated mutant MHC promoters lacking one or the other thyroid response element (TRE-1 and -2). In transgenic mouse hearts, V1 decorated cytoskeletal elements and inhibited ischemia-induced PKC translocation. At high levels, V1 expression was uniformly lethal, with depressed cardiac contractile function, increased expression of fetal cardiac genes, and formation of intracardiomyocyte protein aggregates. Ultrastructural and immunoconfocal analyses of these aggregates revealed focal cytoskeletal disruptions and localized concentrations of desmin and B-crystallin. In individual cardiomyocytes, cytoskeletal abnormalities correlated with impaired contractile function. Whereas desmin and B-crystallin protein were increased 
4-fold in V1 hearts, combined overexpression of these proteins at these levels was not sufficient to cause any detectable cardiac pathology. At low levels, V1 expression conferred striking resistance to postischemic dysfunction, with no measurable effects on basal cardiac structure, function, or gene expression. Intermediate expression of V1 conferred modest basal contractile depression with less ischemic protection, associated with abnormal cardiac gene expression, and a histological picture of infrequent cardiomyocyte cytoskeletal deformities. These results validate an approach of PKC inhibition to protect against myocardial ischemia, but indicate that there is a threshold level of PKC activation that is necessary to maintain normal cardiomyocyte cytoskeletal integrity.
Key Words: ischemia/reperfusion • protein kinase C • myofibrillar cardiomyopathy • congestive heart failure
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