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Cardiovascular Research Advance Access [Accepted Manuscript] published online on September 19, 2007
Cardiovascular Research, doi:10.1093/cvr/cvm022
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Pro-oxidant Effect of Transforming Growth Factor-ß1 Mediates Contractile Dysfunction in Rat Ventricular Myocytes

Shumin Li1, Xun Li1,2, Hong Zheng1, Bin Xie1, Keshore R. Bidasee3 and George J. Rozanski1,4,

1 Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, Nebraska
2 Department of Cardiology, The First Affiliated Hospital, Soochow University, Suzhou, Jiangsu 215006, P.R. China
3 Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska
4 Center for Redox Biology, University of Nebraska-Lincoln, Lincoln, Nebraska

Address for proofs and reprint requests: George J. Rozanski, Ph.D. Department of Cellular and Integrative Physiology, University of Nebraska College of Medicine, 984575 Nebraska Medical Center, Omaha, NE 68198-4575, (402) 559-6056, FAX# (402) 559-4438, email: grozansk{at}unmc.edu

Objective: Transforming growth factor-ß1 (TGF-ß1) is a multifunctional cytokine that contributes to pathogenic cardiac remodeling via mechanisms that involve oxidative stress. However, the direct impact of TGF-ß1 on contractile function of ventricular myocytes is incompletely understood.

Methods: Reactive oxygen species (ROS) production and intracellular glutathione (GSH) were measured by fluorescence microscopy in isolated rat ventricular myocytes pre-treated with TGF-ß1 (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.

Results: TGF-ß1 (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), while fractional shortening was not altered. Ca2+ transients in TGF-ß1-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-ß1 were prevented by an NAD(P)H oxidase inhibitor or a free radical scavenger, both of which significantly mitigated TGF-ß1-induced myocyte contractile dysfunction. Moreover, pre-treating myocytes with exogenous GSH or the GSH precursor N-acetylcysteine also prevented myocyte contractile impairment and abnormal Ca2+ transients elicited by TGF-ß1.

Conclusion: Our data suggest that TGF-ß1-induced cardiomyocyte contractile dysfunction is associated with enhanced ROS production and oxidative alterations in Ca2+ handling proteins regulated by endogenous GSH.

Time for primary review: 27 days


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Home page
 Exp PhysiolHome page
S. Li, M.-Q. Zheng, and G. J. Rozanski
Glutathione homeostasis in ventricular myocytes from rat hearts with chronic myocardial infarction
Exp Physiol, July 1, 2009; 94(7): 815 - 824.
[Abstract] [Full Text] [PDF]


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