title: Profilin modulates sarcomeric organization and mediates cardiomyocyte hypertrophy.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Medicine, Division of Cardiology, The Johns Hopkins University, Baltimore, MD, USA National Heart and Lung Institute, Imperial College London, 4th floor, ICTEM, Hammersmith Campus, Du Cane Road, London W12 0NN, UK v.kooij@imperial.ac.uk.
authors.forename: Viola
authors.initials: V
authors.lastname: Kooij
authors.affiliation: Department of Medicine, Division of Cardiology, The Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Meera C
authors.initials: MC
authors.lastname: Viswanathan
authors.affiliation: Department of Medicine, Division of Cardiology, The Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Dong I
authors.initials: DI
authors.lastname: Lee
authors.affiliation: Department of Medicine, Division of Cardiology, The Johns Hopkins University, Baltimore, MD, USA Division of Cardiology, Medical University of Graz, Graz, Austria.
authors.forename: Peter P
authors.initials: PP
authors.lastname: Rainer
authors.affiliation: Department of Medicine, Division of Cardiology, The Johns Hopkins University, Baltimore, MD, USA.
authors.forename: William
authors.initials: W
authors.lastname: Schmidt
authors.affiliation: Department of Biology, San Diego State University, San Diego, CA, USA.
authors.forename: William A
authors.initials: WA
authors.lastname: Kronert
authors.affiliation: National Heart and Lung Institute, Imperial College London, 4th floor, ICTEM, Hammersmith Campus, Du Cane Road, London W12 0NN, UK.
authors.forename: Sian E
authors.initials: SE
authors.lastname: Harding
authors.affiliation: Department of Medicine, Division of Cardiology, The Johns Hopkins University, Baltimore, MD, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Kass
authors.affiliation: Department of Biology, San Diego State University, San Diego, CA, USA.
authors.forename: Sanford I
authors.initials: SI
authors.lastname: Bernstein
authors.affiliation: Department of Medicine, Division of Cardiology, The Johns Hopkins University, Baltimore, MD, USA Advanced Clinical Biosystems Research Institute, Heart Institute and Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Van Eyk
authors.affiliation: Department of Medicine, Division of Cardiology, The Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Cammarato
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000235:genetics* / Q000378:metabolism*; D004331:Drosophila melanogaster; D019332:Endothelin-1 / Q000378:metabolism; D006333:Heart Failure / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D009210:Myofibrils / Q000378:metabolism; D010656:Phenylephrine / Q000494:pharmacology; D051304:Profilins / Q000235:genetics* / Q000378:metabolism*; D012518:Sarcomeres / Q000378:metabolism
chemical_list: D019332:Endothelin-1; D051304:Profilins; D010656:Phenylephrine
keywords: Cardiac hypertrophy; Cardiomyocyte; Profilin-1; Sarcomere remodelling; chickadee