Extracellular superoxide dismutase protects the heart against oxidative stress and hypertrophy after myocardial infarction.
Extracellular superoxide dismutase (EC-SOD) contributes only a small fraction to total SOD activity in the heart but is strategically located to scavenge free radicals in the extracellular compartment. EC-SOD expression is decreased in myocardial-infarction (MI)-induced heart failure, but whether EC-SOD can abrogate oxidative stress or modify MI-induced ventricular remodeling has not been previously studied. Consequently, the effects of EC-SOD gene deficiency (EC-SOD KO) on left ventricular (LV) oxidative stress, hypertrophy, and fibrosis were studied in EC-SOD KO and wild-type mice under control conditions, and at 4 and 8 weeks after permanent coronary artery ligation. EC-SOD KO had no detectable effect on LV function in normal hearts but caused small but significant increases of LV fibrosis. At 8 weeks after MI, EC-SOD KO mice developed significantly more LV hypertrophy (LV mass increased 1.64-fold in KO mice compared to 1.35-fold in wild-type mice; p<0.01) and more fibrosis and myocyte hypertrophy which was more prominent in the peri-infarct region than in the remote myocardium. EC-SOD KO mice had greater increases of nitrotyrosine in the peri-infarct myocardium, and this was associated with a greater reduction of LV ejection fraction, a greater decrease of sarcoplasmic or endoplasmic reticulum calcium2+ ATPase, and a greater increase of atrial natriuretic peptide in the peri-infarct zone compared to wild-type mice. EC-SOD KO was associated with more increases of phosphorylated p38 (p-p38(Thr180/Tyr182)), p42/44 extracellular signal-regulated kinase (p-Erk(Thr202/Tyr204)), and c-Jun N-terminal kinase (p-JNK(Thr183/Tyr185)) both under control conditions and after MI, indicating that EC-SOD KO increases activation of mitogen-activated protein kinase signaling pathways. These findings demonstrate that EC-SOD plays an important role in protecting the heart against oxidative stress and infarction-induced ventricular hypertrophy.
van Deel
Elza D
ED
Center for Vascular Biology and Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
Lu
Zhongbing
Z
Xu
Xin
X
Zhu
Guangshuo
G
Hu
Xinli
X
Oury
Tim D
TD
Bache
Robert J
RJ
Duncker
Dirk J
DJ
Chen
Yingjie
Y
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000473:pathology; D004452:Echocardiography / Q000379:methods; D005109:Extracellular Matrix / Q000201:enzymology* / Q000378:metabolism; D005355:Fibrosis; D006321:Heart / Q000502:physiology*; D006984:Hypertrophy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000473:pathology*; D009206:Myocardium / Q000473:pathology; D018384:Oxidative Stress; D013482:Superoxide Dismutase / Q000378:metabolism*
C499090:Sod3 protein, mouse; D013482:Superoxide Dismutase; D000251:Adenosine Triphosphatases