Pro-oxidant effect of transforming growth factor-β1 mediates contractile dysfunction in rat ventricular myocytes

Shumin Li, Xun Li, Hong Zheng, Bin Xie, Keshore R. Bidasee, George J. Rozanski

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

Aims: Transforming growth factor-β1 (TGF- β1) is a multifunctional cytokine that contributes to pathogenic cardiac remodelling via mechanisms that involve oxidative stress. However, the direct impact of TGF-β1 on contractile function of ventricular myocytes is incompletely understood. Methods and results: Reactive oxygen species (ROS) production and intracellular glutathione (GSH) were measured by fluorescence microscopy in isolated rat ventricular myocytes pretreated with TGF-β1 (0.1-10 ng/mL). In separate studies, video edge detection measurements were made to evaluate myocyte contractile function, and confocal microscopy was used to monitor evoked Ca2+ transients. TGF-β1 (1 ng/mL) for 3-4 h significantly increased ROS production by 90% (P < 0.05) and decreased GSH by 34% (P < 0.05) compared with control. These changes paralleled a significant decrease in the rate of myocyte shortening and relaxation by 33% and 43%, respectively (0.5 Hz; P < 0.05), whereas fractional shortening was not altered. Ca2+ transients in TGF-β1-treated myocytes were characterized by a delayed peak and slowing in the rate of decay but no change in peak Ca2+ amplitude. Increased ROS production and GSH depletion by TGF-β1 were prevented by an NAD(P)H oxidase inhibitor or a free radical scavenger, both of which significantly mitigated TGF-β1-induced myocyte contractile dysfunction. Moreover, pretreating myocytes with exogenous GSH or the GSH precursor N-acetylcysteine also prevented myocyte contractile impairment and abnormal Ca2+ transients elicited by TGF-β1. Conclusion: Our data suggest that TGF-β1-induced cardiomyocyte contractile dysfunction is associated with enhanced ROS production and oxidative alterations in Ca2+ handling proteins regulated by endogenous GSH.

Original languageEnglish (US)
Pages (from-to)107-117
Number of pages11
JournalCardiovascular research
Volume77
Issue number1
DOIs
StatePublished - Jan 1 2008

Keywords

  • Glutathione
  • NAD(P)H oxidase
  • Oxidative stress
  • Redox
  • TGF

ASJC Scopus subject areas

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

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