title: Activation of HuR downstream of p38 MAPK promotes cardiomyocyte hypertrophy.
abstract: The RNA binding protein Human antigen R (HuR) interacts with specific AU-rich domains in target mRNAs and is highly expressed in many cell types, including cardiomyocytes. However, the role of HuR in cardiac physiology is largely unknown. Our results show that HuR undergoes cytoplasmic translocation, indicative of its activation, in hypertrophic cardiac myocytes. Specifically, HuR cytoplasmic translocation is significantly increased in NRVMs (neonatal rat ventricular myocytes) following treatment with phenylephrine or angiotensin II, agonists of two independent Gαq-coupled GPCRs known to induce hypertrophy. This Gq-mediated HuR activation is dependent on p38 MAP kinase, but not canonical Gq-PKC signaling. Furthermore, we show that HuR activation is necessary for Gq-mediated hypertrophic growth of NRVMs as siRNA-mediated knockdown of HuR inhibits hypertrophy as measured by cell size and expression of ANF (atrial natriuretic factor). Additionally, HuR overexpression is sufficient to induce hypertrophic cell growth. To decipher the downstream mechanisms by which HuR translocation promotes cardiomyocyte hypertrophy, we assessed the role of HuR in the transcriptional activity of NFAT (nuclear factor of activated T cells), the activation of which is a hallmark of cardiac hypertrophy. Using an NFAT-luciferase reporter assay, we show an acute inhibition of NFAT transcriptional activity following pharmacological inhibition of HuR. In conclusion, our results identify HuR as a novel mediator of cardiac hypertrophy downstream of the Gq-p38 MAPK pathway, and suggest modulation of NFAT activity as a potential mechanism.
authors: Division of Cardiovascular Health and Disease, University of Cincinnati College of Medicine, Cincinnati, OH, United States.
authors: Samuel
authors: S
authors: Slone
authors: Division of Cardiovascular Health and Disease, University of Cincinnati College of Medicine, Cincinnati, OH, United States.
authors: Sarah R
authors: SR
authors: Anthony
authors: Department of Molecular Biosciences, University of Kansas, Lawrence, KS, United States.
authors: Xiaoqing
authors: X
authors: Wu
authors: Department of Biological Sciences, McMicken College of Arts and Sciences, University of Cincinnati, Cincinnati, OH, United States.
authors: Joshua B
authors: JB
authors: Benoit
authors: Department of Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, United States.
authors: Jeffrey
authors: J
authors: Aube
authors: Department of Molecular Biosciences, University of Kansas, Lawrence, KS, United States.
authors: Liang
authors: L
authors: Xu
authors: Division of Cardiovascular Health and Disease, University of Cincinnati College of Medicine, Cincinnati, OH, United States. Electronic address: Michael.Tranter@UC.edu.
authors: Michael
authors: M
authors: Tranter
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D009320:Atrial Natriuretic Factor / Q000378:metabolism; D006332:Cardiomegaly / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D000067780:ELAV-Like Protein 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D055785:Gene Knockdown Techniques; D032383:Myocytes, Cardiac / Q000201:enzymology* / Q000473:pathology*; D050778:NFATC Transcription Factors / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D015533:Transcriptional Activation / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D000067780:ELAV-Like Protein 1; D050778:NFATC Transcription Factors; D009320:Atrial Natriuretic Factor; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Heart; HuR; Hypertrophy; RNA binding protein; p38 MAPK