Rosiglitazone promotes cardiac hypertrophy and alters chromatin remodeling in isolated cardiomyocytes

Toxicol Lett. 2017 Oct 5;280:151-158. doi: 10.1016/j.toxlet.2017.08.011. Epub 2017 Aug 16.

Abstract

Rosiglitazone is an anti-diabetic agent that raised a major controversy over its cardiovascular adverse effects. There is in vivo evidence that Rosiglitazone promotes cardiac hypertrophy by PPAR-γ-independent mechanisms. However, whether Rosiglitazone directly alters hypertrophic growth in cardiac cells is unknown. Chromatin remodeling by histone post-translational modifications has emerged as critical for many cardiomyopathies. Based on these observations, this study was initiated to investigate the cardiac hypertrophic effect of Rosiglitazone in a cellular model of primary neonatal rat cardiomyocytes (NRCM). We assessed whether the drug alters cardiac hypertrophy and its relationship with histone H3 phosphorylation. Our study showed that Rosiglitazone is a mild pro-hypertrophic agent. Rosiglitazone caused a significant increase in the release of brain natriuretic peptide (BNP) into the cell media and also increased cardiomyocytes surface area and atrial natriuretic peptide (ANP) protein expression significantly. These changes correlated with increased cardiac phosphorylation of p38 MAPK and enhanced phosphorylation of H3 at serine 10 globally and at one cardiac hypertrophic gene locus. These results demonstrate that Rosiglitazone causes direct cardiac hypertrophy in NRCM and alters H3 phosphorylation status. They suggest a new mechanism of Rosiglitazone cardiotoxicity implicating chromatin remodeling secondary to H3 phosphorylation, which activate the fetal cardiac gene program.

Keywords: Cardiac hypertrophy; Chromatin remodeling; Rosiglitazone.

MeSH terms

  • Animals
  • Atrial Natriuretic Factor / metabolism
  • Cardiomegaly / chemically induced*
  • Chromatin Assembly and Disassembly / drug effects*
  • Epigenesis, Genetic
  • Female
  • Fibrinolytic Agents / administration & dosage
  • Fibrinolytic Agents / toxicity*
  • Gene Expression Regulation / drug effects
  • Histones / metabolism
  • Myocytes, Cardiac / cytology
  • Myocytes, Cardiac / drug effects*
  • Myocytes, Cardiac / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Rosiglitazone
  • Thiazolidinediones / administration & dosage
  • Thiazolidinediones / toxicity*
  • p38 Mitogen-Activated Protein Kinases / genetics
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Fibrinolytic Agents
  • Histones
  • Thiazolidinediones
  • Rosiglitazone
  • Atrial Natriuretic Factor
  • p38 Mitogen-Activated Protein Kinases