Ischemic protection and myofibrillar cardiomyopathy: Dose-dependent effects of in vivo δPKC inhibition

Harvey S. Hahn, Martin G. Yussman, Tsuyoshi Toyokawa, Yehia Marreez, Thomas J. Barrett, K. Chad Hilty, Hanna Osinska, Jeffrey Robbins, Gerald W. Dorn

Research output: Contribution to journalArticlepeer-review

72 Scopus citations

Abstract

To delineate the in vivo cardiac functions requiring normal δ protein kinase C (PKC) activity, we pursued loss-of-function through transgenic expression of a δPKC-specific translocation inhibitor protein fragment, δV1, in mouse hearts. Initial results using the mouse α-myosin heavy chain (αMHC) promoter resulted in a lethal heart failure phenotype. Viable δV1 mice were therefore obtained using novel attenuated mutant αMHC promoters lacking one or the other thyroid response element (TRE-1 and -2). In transgenic mouse hearts, δV1 decorated cytoskeletal elements and inhibited ischemia-induced δPKC translocation. At high levels, δV1 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 αB-crystallin. In individual cardiomyocytes, cytoskeletal abnormalities correlated with impaired contractile function. Whereas desmin and αB-crystallin protein were increased ≈4-fold in δV1 hearts, combined overexpression of these proteins at these levels was not sufficient to cause any detectable cardiac pathology. At low levels, δV1 expression conferred striking resistance to postischemic dysfunction, with no measurable effects on basal cardiac structure, function, or gene expression. Intermediate expression of δV1 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 δPKC inhibition to protect against myocardial ischemia, but indicate that there is a threshold level of δPKC activation that is necessary to maintain normal cardiomyocyte cytoskeletal integrity.

Original languageEnglish
Pages (from-to)741-748
Number of pages8
JournalCirculation research
Volume91
Issue number8
DOIs
StatePublished - Oct 18 2002

Keywords

  • Congestive heart failure
  • Ischemia/reperfusion
  • Myofibrillar cardiomyopathy
  • Protein kinase C

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