Profilin modulates sarcomeric organization and mediates cardiomyocyte hypertrophy

Viola Kooij, Meera C. Viswanathan, Dong I. Lee, Peter P. Rainer, William Schmidt, William A. Kronert, Sian E. Harding, David A. Kass, Sanford I. Bernstein, Jennifer E. Van Eyk, Anthony Cammarato

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)238-248
Number of pages11
JournalCardiovascular research
Volume110
Issue number2
DOIs
StatePublished - May 15 2016

Keywords

  • Cardiac hypertrophy
  • Cardiomyocyte
  • Profilin-1
  • Sarcomere remodelling
  • chickadee

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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