TY - JOUR
T1 - Polycystin-1 is a cardiomyocyte mechanosensor that governs L-type Ca2+ channel protein stability
AU - Pedrozo, Zully
AU - Criollo, Alfredo
AU - Battiprolu, Pavan K.
AU - Morales, Cyndi R.
AU - Contreras-Ferrat, Ariel
AU - Fernández, Carolina
AU - Jiang, Nan
AU - Luo, Xiang
AU - Caplan, Michael J.
AU - Somlo, Stefan
AU - Rothermel, Beverly A
AU - Gillette, Thomas G.
AU - Lavandero, Sergio
AU - Hill, Joseph A
N1 - Publisher Copyright:
© 2015 American Heart Association, Inc.
PY - 2015/6/16
Y1 - 2015/6/16
N2 - 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.
AB - 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.
KW - Cardiomegaly
KW - Cellular
KW - Mechanotransduction
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U2 - 10.1161/CIRCULATIONAHA.114.013537
DO - 10.1161/CIRCULATIONAHA.114.013537
M3 - Article
C2 - 25888683
AN - SCOPUS:84936119043
SN - 0009-7322
VL - 131
SP - 2131
EP - 2142
JO - Circulation
JF - Circulation
IS - 24
ER -