Polycystin-1 is a cardiomyocyte mechanosensor that governs L-type Ca2+ channel protein stability

Zully Pedrozo, Alfredo Criollo, Pavan K. Battiprolu, Cyndi R. Morales, Ariel Contreras-Ferrat, Carolina Fernández, Nan Jiang, Xiang Luo, Michael J. Caplan, Stefan Somlo, Beverly A Rothermel, Thomas G. Gillette, Sergio Lavandero, Joseph A Hill

Research output: Contribution to journalArticlepeer-review

39 Scopus citations

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 hypoosmotic 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.

Original languageEnglish (US)
Pages (from-to)2131-2142
Number of pages12
JournalCirculation
Volume131
Issue number24
DOIs
StatePublished - Jun 16 2015

Keywords

  • Cardiomegaly
  • Cellular
  • Mechanotransduction

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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