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J Gen Physiol. 2019 Jul 31. pii: jgp.201912353. doi: 10.1085/jgp.201912353. [Epub ahead of print]

Cardiac contractile dysfunction and protein kinase C-mediated myofilament phosphorylation in disease and aging.

Author information

1
Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, MI.
2
Department of Cardiac Surgery, University of Michigan, Ann Arbor, MI.
3
Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, MI wfall@umich.edu.

Abstract

Increases in protein kinase C (PKC) are associated with diminished cardiac function, but the contribution of downstream myofilament phosphorylation is debated in human and animal models of heart failure. The current experiments evaluated PKC isoform expression, downstream cardiac troponin I (cTnI) S44 phosphorylation (p-S44), and contractile function in failing (F) human myocardium, and in rat models of cardiac dysfunction caused by pressure overload and aging. In F human myocardium, elevated PKCα expression and cTnI p-S44 developed before ventricular assist device implantation. Circulatory support partially reduced PKCα expression and cTnI p-S44 levels and improved cellular contractile function. Gene transfer of dominant negative PKCα (PKCαDN) into F human myocytes also improved contractile function and reduced cTnI p-S44. Heightened cTnI phosphorylation of the analogous residue accompanied reduced myocyte contractile function in a rat model of pressure overload and in aged Fischer 344 × Brown Norway F1 rats (≥26 mo). Together, these results indicate PKC-targeted cTnI p-S44 accompanies cardiac cellular dysfunction in human and animal models. Interfering with PKCα activity reduces downstream cTnI p-S44 levels and partially restores function, suggesting cTnI p-S44 may be a useful target to improve contractile function in the future.

PMID:
31366607
DOI:
10.1085/jgp.201912353

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