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Circulation. 2015 Jun 16;131(24):2131-42. doi: 10.1161/CIRCULATIONAHA.114.013537. Epub 2015 Apr 17.

Polycystin-1 Is a Cardiomyocyte Mechanosensor That Governs L-Type Ca2+ Channel Protein Stability.

Author information

  • 1From Division of Cardiology, Department of Internal Medicine (Z.P., A.C., P.K.B., C.R.M., N.J., X.L., B.A.R., T.G.G., S.L., J.A.H.) and Department of Molecular Biology (B.A.R., J.A.H.), UT Southwestern Medical Center, Dallas, TX; Advanced Center for Chronic Diseases and Centro de Estudios Moleculares de la Célula, Facultad de Medicina & Facultad de Ciencias Químicas y Farmacéuticas, Santiago, Chile (Z.P., A.C.-F., C.F., S.L.); Instituto de Ciencias Biomédicas, Facultad de Medicina (Z.P., S.L.) and Instituto de Investigación en Ciencias Odontológicas, Facultad de Odontología (A.C.), Universidad de Chile, Santiago; and Departments of Cellular and Molecular Physiology (M.J.C.), Internal Medicine (S.S.), and Genetics (S.S.), Yale University School of Medicine, New Haven, CT.
  • 2From Division of Cardiology, Department of Internal Medicine (Z.P., A.C., P.K.B., C.R.M., N.J., X.L., B.A.R., T.G.G., S.L., J.A.H.) and Department of Molecular Biology (B.A.R., J.A.H.), UT Southwestern Medical Center, Dallas, TX; Advanced Center for Chronic Diseases and Centro de Estudios Moleculares de la Célula, Facultad de Medicina & Facultad de Ciencias Químicas y Farmacéuticas, Santiago, Chile (Z.P., A.C.-F., C.F., S.L.); Instituto de Ciencias Biomédicas, Facultad de Medicina (Z.P., S.L.) and Instituto de Investigación en Ciencias Odontológicas, Facultad de Odontología (A.C.), Universidad de Chile, Santiago; and Departments of Cellular and Molecular Physiology (M.J.C.), Internal Medicine (S.S.), and Genetics (S.S.), Yale University School of Medicine, New Haven, CT. joseph.hill@utsouthwestern.edu slavander@uchile.cl.

Abstract

BACKGROUND:

L-type calcium channel activity is critical to afterload-induced hypertrophic growth of the heart. However, the mechanisms governing mechanical stress-induced activation of L-type calcium channel activity are obscure. Polycystin-1 (PC-1) is a G protein-coupled receptor-like protein that functions as a mechanosensor in a variety of cell types and is present in cardiomyocytes.

METHODS AND RESULTS:

We subjected neonatal rat ventricular myocytes to mechanical stretch by exposing them to hypo-osmotic medium or cyclic mechanical stretch, triggering cell growth in a manner dependent on L-type calcium channel activity. RNAi-dependent knockdown of PC-1 blocked this hypertrophy. Overexpression of a C-terminal fragment of PC-1 was sufficient to trigger neonatal rat ventricular myocyte hypertrophy. Exposing neonatal rat ventricular myocytes to hypo-osmotic medium resulted in an increase in α1C protein levels, a response that was prevented by PC-1 knockdown. MG132, a proteasomal inhibitor, rescued PC-1 knockdown-dependent declines in α1C protein. To test this in vivo, we engineered mice harboring conditional silencing of PC-1 selectively in cardiomyocytes (PC-1 knockout) and subjected them to mechanical stress in vivo (transverse aortic constriction). At baseline, PC-1 knockout mice manifested decreased cardiac function relative to littermate controls, and α1C L-type calcium channel protein levels were significantly lower in PC-1 knockout hearts. Whereas control mice manifested robust transverse aortic constriction-induced increases in cardiac mass, PC-1 knockout mice showed no significant growth. Likewise, transverse aortic constriction-elicited increases in hypertrophic markers and interstitial fibrosis were blunted in the knockout animals

CONCLUSION:

PC-1 is a cardiomyocyte mechanosensor that is required for cardiac hypertrophy through a mechanism that involves stabilization of α1C protein.

KEYWORDS:

cardiomegaly; mechanotransduction, cellular

PMID:
25888683
PMCID:
PMC4470854
DOI:
10.1161/CIRCULATIONAHA.114.013537
[PubMed - indexed for MEDLINE]
Free PMC Article

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