Abstract 14150: Polycystin-1 Regulates Cardiac Hypertrophy via the L-type Calcium Channel
Background: Increases in L-type calcium channel (LTCC) activity are critical to load-induced cardiomyocyte hypertrophy. Yet, underlying mechanisms are unknown. Polycystin-1 (PC1) functions as a mechanosensor in a number of cell types and is present in cardiomyocytes. We hypothesized that PC1 is a mechanosensor in heart and regulates LTCC activity and cardiac hypertrophy.
Methods and Results: Mechanical stress was induced both in vivo, using transverse aortic constriction (TAC), and in vitro using hypo-osmotic solution (HS). Whereas control mice manifested robust TAC-induced increases in cardiac mass (HW/BW increased 80%; from 4.2±0.2 mg/g to 7.6±1.4, n=8-10, p<0.05), PC1 KO (α-MHC-Cre, pKD1f/f) mice manifested no significant growth (HW/BW increased 27%; from 4.3±0.4 to 5.4±1.0, n=8-9, p>0.05). Likewise, increases in hypertrophic markers (β-MHC, BNP, ANF and RCAN mRNA) were blunted in the knockout animals. At baseline, PC1 KO mice manifested decreased cardiac function (%FS 65%±4 WT versus 40%±3 KO, p<0.0001). HS stimulation induced hypertrophy in cultured neonatal rat ventricular myocytes (NRVM) in a manner dependent on LTCC activity. RNAi-dependent knockdown of PC1 blocked this hypertrophy. Conversely, over-expression of a C-terminal fragment of PC1 was sufficient to trigger NRVM hypertrophy. α1C LTCC protein levels in vivo were significantly lower in PC1 KO hearts. HS stimulation of NRVMs provoked an increase in α1C protein levels, a response which was prevented by PC1 knockdown. MG132, a proteasomal inhibitor, rescued HS-induced increases in α1C protein levels despite PC1 knockdown.
Conclusion: Polycystin-1 is a novel cardiomyocyte mechanosensor which functions to stabilize α1C protein.
- © 2013 by American Heart Association, Inc.