title: Detrimental effect of combined exercise training and eNOS overexpression on cardiac function after myocardial infarction.
abstract: 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 Ca(2+)-sensitivity and sarco(endo)plasmic reticulum Ca(2+)-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 Ca(2+) 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."
authors.affiliation: Div. of Experimental Cardiology, Dept. of Cardiology, Thoraxcenter, Erasmus Univ. Medical Center, PO Box 2040, Rotterdam 3000 CA, The Netherlands.
authors.forename: Monique C
authors.initials: MC
authors.lastname: de Waard
authors.forename: Jolanda
authors.initials: J
authors.lastname: van der Velden
authors.forename: Nicky M
authors.initials: NM
authors.lastname: Boontje
authors.forename: Dick H W
authors.initials: DH
authors.lastname: Dekkers
authors.forename: Rien
authors.initials: R
authors.lastname: van Haperen
authors.forename: Diederik W D
authors.initials: DW
authors.lastname: Kuster
authors.forename: Jos M J
authors.initials: JM
authors.lastname: Lamers
authors.forename: Rini
authors.initials: R
authors.lastname: de Crom
authors.forename: Dirk J
authors.initials: DJ
authors.lastname: Duncker
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D008841:Actin Cytoskeleton / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001120:Arginine / Q000378:metabolism; D001708:Biopterins / Q000031:analogs & derivatives / Q000378:metabolism; D004195:Disease Models, Animal; D005081:Exercise Therapy; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009200:Myocardial Contraction; D009203:Myocardial Infarction / Q000150:complications / Q000201:enzymology / Q000503:physiopathology / Q000628:therapy*; D009206:Myocardium / Q000201:enzymology*; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D010766:Phosphorylation; D005082:Physical Exertion; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation; D018487:Ventricular Dysfunction, Left / Q000201:enzymology / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D017725:Ventricular Pressure; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D000975:Antioxidants; D013481:Superoxides; D001708:Biopterins; D001120:Arginine; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C003402:sapropterin; D000111:Acetylcysteine