TY - JOUR
T1 - Profilin modulates sarcomeric organization and mediates cardiomyocyte hypertrophy
AU - Kooij, Viola
AU - Viswanathan, Meera C.
AU - Lee, Dong I.
AU - Rainer, Peter P.
AU - Schmidt, William
AU - Kronert, William A.
AU - Harding, Sian E.
AU - Kass, David A.
AU - Bernstein, Sanford I.
AU - Van Eyk, Jennifer E.
AU - Cammarato, Anthony
N1 - Funding Information:
This work was supported by American Heart Association post-doctoral fellowship (V.K., 12POST11520006), British Heart Foundation Project Grant (V.K., PG/14/44/30890), National Institutes of Health [W.S., T-32 HL-07227; S.I.B., R01GM32443; J.V.E., P01 HL77189-01; J.V.E.,NHLBI-HV-10-05 (2); and A.C., NHLBI R56HL124091 and R01HL124091], and American Heart Association scientist development grant (A.C., 10SDG4180089).
Publisher Copyright:
© 2016 The Author.
PY - 2016/5/15
Y1 - 2016/5/15
N2 - Aims Heart failure is often preceded by cardiac hypertrophy, which is characterized by increased cell size, altered protein abundance, and actin cytoskeletal reorganization. Profilin is a well-conserved, ubiquitously expressed, multifunctional actin-binding protein, and its role in cardiomyocytes is largely unknown. Given its involvement in vascular hypertrophy, we aimed to test the hypothesis that profilin-1 is a key mediator of cardiomyocyte-specific hypertrophic remodelling. Methods and results Profilin-1 was elevated in multiple mouse models of hypertrophy, and a cardiomyocyte-specific increase of profilin in Drosophila resulted in significantly larger heart tube dimensions. Moreover, adenovirus-mediated overexpression of profilin-1 in neonatal rat ventricular myocytes (NRVMs) induced a hypertrophic response, measured by increased myocyte size and gene expression. Profilin-1 silencing suppressed the response in NRVMs stimulated with phenylephrine or endothelin-1. Mechanistically, we found that profilin-1 regulates hypertrophy, in part, through activation of the ERK1/2 signalling cascade. Confocal microscopy showed that profilin localized to the Z-line of Drosophila myofibrils under normal conditions and accumulated near the M-line when overexpressed. Elevated profilin levels resulted in elongated sarcomeres, myofibrillar disorganization, and sarcomeric disarray, which correlated with impaired muscle function. Conclusion Our results identify novel roles for profilin as an important mediator of cardiomyocyte hypertrophy. We show that overexpression of profilin is sufficient to induce cardiomyocyte hypertrophy and sarcomeric remodelling, and silencing of profilin attenuates the hypertrophic response.
AB - Aims Heart failure is often preceded by cardiac hypertrophy, which is characterized by increased cell size, altered protein abundance, and actin cytoskeletal reorganization. Profilin is a well-conserved, ubiquitously expressed, multifunctional actin-binding protein, and its role in cardiomyocytes is largely unknown. Given its involvement in vascular hypertrophy, we aimed to test the hypothesis that profilin-1 is a key mediator of cardiomyocyte-specific hypertrophic remodelling. Methods and results Profilin-1 was elevated in multiple mouse models of hypertrophy, and a cardiomyocyte-specific increase of profilin in Drosophila resulted in significantly larger heart tube dimensions. Moreover, adenovirus-mediated overexpression of profilin-1 in neonatal rat ventricular myocytes (NRVMs) induced a hypertrophic response, measured by increased myocyte size and gene expression. Profilin-1 silencing suppressed the response in NRVMs stimulated with phenylephrine or endothelin-1. Mechanistically, we found that profilin-1 regulates hypertrophy, in part, through activation of the ERK1/2 signalling cascade. Confocal microscopy showed that profilin localized to the Z-line of Drosophila myofibrils under normal conditions and accumulated near the M-line when overexpressed. Elevated profilin levels resulted in elongated sarcomeres, myofibrillar disorganization, and sarcomeric disarray, which correlated with impaired muscle function. Conclusion Our results identify novel roles for profilin as an important mediator of cardiomyocyte hypertrophy. We show that overexpression of profilin is sufficient to induce cardiomyocyte hypertrophy and sarcomeric remodelling, and silencing of profilin attenuates the hypertrophic response.
KW - Cardiac hypertrophy
KW - Cardiomyocyte
KW - Profilin-1
KW - Sarcomere remodelling
KW - chickadee
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U2 - 10.1093/cvr/cvw050
DO - 10.1093/cvr/cvw050
M3 - Article
C2 - 26956799
AN - SCOPUS:84966538951
SN - 0008-6363
VL - 110
SP - 238
EP - 248
JO - Cardiovascular Research
JF - Cardiovascular Research
IS - 2
ER -