title: Extracellular superoxide dismutase deficiency exacerbates pressure overload-induced left ventricular hypertrophy and dysfunction.
abstract: Extracellular superoxide dismutase (SOD) contributes only a small fraction to total SOD activity in the normal heart but is strategically located to scavenge free radicals in the extracellular compartment. To examine the physiological significance of extracellular SOD in the response of the heart to hemodynamic stress, we studied the effect of extracellular SOD deficiency on transverse aortic constriction (TAC)-induced left ventricular remodeling. Under unstressed conditions extracellular SOD deficiency had no effect on myocardial total SOD activity, the ratio of glutathione:glutathione disulfide, nitrotyrosine content, or superoxide anion production but resulted in small but significant increases in myocardial fibrosis and ventricular mass. In response to TAC for 6 weeks, extracellular SOD-deficient mice developed more severe left ventricular hypertrophy (heart weight increased 2.56-fold in extracellular SOD-deficient mice as compared with 1.99-fold in wild-type mice) and pulmonary congestion (lung weight increased 2.92-fold in extracellular SOD-deficient mice as compared with 1.84-fold in wild-type mice). Extracellular SOD-deficient mice also had more ventricular fibrosis, dilation, and a greater reduction of left ventricular fractional shortening and rate of pressure development after TAC. TAC resulted in greater increases of ventricular collagen I, collagen III, matrix metalloproteinase-2, matrix metalloproteinase-9, nitrotyrosine, and superoxide anion production. TAC also resulted in a greater decrease of the ratio of glutathione:glutathione disulfide in extracellular SOD-deficient mice. The finding that extracellular SOD deficiency had minimal impact on myocardial overall SOD activity but exacerbated TAC induced myocardial oxidative stress, hypertrophy, fibrosis, and dysfunction indicates that the distribution of extracellular SOD in the extracellular space is critically important in protecting the heart against pressure overload.
authors.affiliation: Center for Vascular Biology, Department of Medicine, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
authors.forename: Zhongbing
authors.initials: Z
authors.lastname: Lu
authors.forename: Xin
authors.initials: X
authors.lastname: Xu
authors.forename: Xinli
authors.initials: X
authors.lastname: Hu
authors.forename: Guangshuo
authors.initials: G
authors.lastname: Zhu
authors.forename: Ping
authors.initials: P
authors.lastname: Zhang
authors.forename: Elza D
authors.initials: ED
authors.lastname: van Deel
authors.forename: Joel P
authors.initials: JP
authors.lastname: French
authors.forename: John T
authors.initials: JT
authors.lastname: Fassett
authors.forename: Tim D
authors.initials: TD
authors.lastname: Oury
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Bache
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Chen
mesh_terms: D000818:Animals; D005355:Fibrosis / Q000209:etiology / Q000378:metabolism; D006333:Heart Failure / Q000378:metabolism; D006352:Heart Ventricles / Q000473:pathology / Q000503:physiopathology; D006973:Hypertension / Q000150:complications / Q000378:metabolism; D017379:Hypertrophy, Left Ventricular / Q000201:enzymology* / Q000209:etiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000502:physiology; D018384:Oxidative Stress / Q000502:physiology; D013482:Superoxide Dismutase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000201:enzymology* / Q000209:etiology
chemical_list: C499090:Sod3 protein, mouse; D013482:Superoxide Dismutase