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This Article Full Text Full Text (PDF) All Versions of this Article: 296/5/H1513    most recent 00485.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by de Waard, M. C. Articles by Duncker, D. J. Search for Related Content PubMed PubMed Citation Articles by de Waard, M. C. Articles by Duncker, D. J.

Detrimental effect of combined exercise training and eNOS overexpression on cardiac function after myocardial infarction

¹Experimental Cardiology, Department of Cardiology, Thoraxcenter, Erasmus University Medical Center, Rotterdam; ²Laboratory for Physiology, Free University Medical Center, Amsterdam; and Departments of ³Biochemistry, ⁴Cell Biology and Genetics, and ⁵Vascular Surgery, Erasmus University Medical Center, Rotterdam, The Netherlands

Submitted 9 May 2008 ; accepted in final form 26 February 2009

It has been reported that exercise after myocardial infarction (MI) attenuates left ventricular (LV) pump dysfunction by normalization of myofilament function. This benefit could be due to an exercise-induced upregulation of endothelial nitric oxide synthase (eNOS) expression and activity. Consequently, we first tested the hypothesis that the effects of exercise after MI can be mimicked by elevated eNOS expression using transgenic mice with overexpression of human eNOS (eNOSTg). Both exercise and eNOSTg attenuated LV remodeling and dysfunction after MI in mice and improved cardiomyocyte maximal force development (F_max). However, only exercise training restored myofilament Ca²⁺-sensitivity and sarco(endo)plasmic reticulum Ca²⁺-ATPase (SERCA)2a protein levels and improved the first derivative of LV pressure at 30 mmHg. Conversely, only eNOSTg improved survival. In view of these partly complementary actions, we subsequently tested the hypothesis that combining exercise and eNOSTg would provide additional protection against LV remodeling and dysfunction after MI. Unexpectedly, the combination of exercise and eNOSTg abolished the beneficial effects on LV remodeling and dysfunction of either treatment alone. The latter was likely due to perturbations in Ca²⁺ homeostasis, as myofilament F_max actually increased despite marked reductions in the phosphorylation status of several myofilament proteins, whereas the exercise-induced increases in SERCA2a protein levels were lost in eNOSTg mice. Antioxidant treatment with N-acetylcysteine or supplementation of tetrahydrobiopterin and L-arginine prevented these detrimental effects on LV function while partly restoring the phosphorylation status of myofilament proteins and further enhancing myofilament F_max. In conclusion, the combination of exercise and elevated eNOS expression abolished the cardioprotective effects of either treatment alone after MI, which appeared to be, at least in part, the result of increased oxidative stress secondary to eNOS "uncoupling."

left ventricular remodeling; endothelial nitric oxide synthase overexpression

This article has been cited by other articles:

				M. C. de Waard and D. J. Duncker Prior exercise improves survival, infarct healing, and left ventricular function after myocardial infarction J Appl Physiol, September 1, 2009; 107(3): 928 - 936. [Abstract] [Full Text] [PDF]