Profilin modulates sarcomeric organization and mediates cardiomyocyte hypertrophy

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

Research output: Contribution to journalArticle

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

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Profilins
Cardiac Myocytes
Hypertrophy
Muscle Cells
Drosophila
Microfilament Proteins
Sarcomeres
Myofibrils
Cardiomegaly
Phenylephrine
Endothelin-1
Cell Size
Adenoviridae
Confocal Microscopy
Blood Vessels
Actins

Keywords

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

ASJC Scopus subject areas

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

Cite this

Profilin modulates sarcomeric organization and mediates cardiomyocyte hypertrophy. / Kooij, Viola; Viswanathan, Meera C.; Lee, Dong; Rainer, Peter P.; Schmidt, William; Kronert, William A.; Harding, Sian E.; Kass, David A; Bernstein, Sanford I.; Van Eyk, Jennifer E.; Cammarato, Anthony Ross.

In: Cardiovascular Research, Vol. 110, No. 2, 15.05.2016, p. 238-248.

Research output: Contribution to journalArticle

Kooij, V, Viswanathan, MC, Lee, D, Rainer, PP, Schmidt, W, Kronert, WA, Harding, SE, Kass, DA, Bernstein, SI, Van Eyk, JE & Cammarato, AR 2016, 'Profilin modulates sarcomeric organization and mediates cardiomyocyte hypertrophy', Cardiovascular Research, vol. 110, no. 2, pp. 238-248. https://doi.org/10.1093/cvr/cvw050
Kooij V, Viswanathan MC, Lee D, Rainer PP, Schmidt W, Kronert WA et al. Profilin modulates sarcomeric organization and mediates cardiomyocyte hypertrophy. Cardiovascular Research. 2016 May 15;110(2):238-248. https://doi.org/10.1093/cvr/cvw050
Kooij, Viola ; Viswanathan, Meera C. ; Lee, Dong ; Rainer, Peter P. ; Schmidt, William ; Kronert, William A. ; Harding, Sian E. ; Kass, David A ; Bernstein, Sanford I. ; Van Eyk, Jennifer E. ; Cammarato, Anthony Ross. / Profilin modulates sarcomeric organization and mediates cardiomyocyte hypertrophy. In: Cardiovascular Research. 2016 ; Vol. 110, No. 2. pp. 238-248.
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AU - Schmidt, William

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AU - Harding, Sian E.

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AU - Cammarato, Anthony Ross

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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.

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