on November 12, 2007
Published online before print November 12, 2007, doi: 10.1161/HYPERTENSIONAHA.107.098186
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Submitted on July 18, 2007
From the Center for Vascular Biology (Z.L., X.X., G.Z., E.D.v.D., Y.C.), and Cardiovascular Division (Z.L., X.X., X.H., G.Z., P.Z., J.P.F., J.T.F., R.J.B., Y.C.), Department of Medicine, University of Minnesota Medical School, Minneapolis; Department of Pathology (T.D.O.), University of Pittsburgh Medical Center, University of Pittsburgh, Pa; and the Division of Experimental Cardiology (E.D.v.D.), Department of Cardiology, Cardiovascular Research School COEUR, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands. * To whom correspondence should be addressed. E-mail: chenx106{at}tc.umn.edu.
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.
Revised on July 24, 2007
Extracellular Superoxide Dismutase Deficiency Exacerbates Pressure Overload–Induced Left Ventricular Hypertrophy and Dysfunction
Zhongbing Lu;
Key words: extracellular SOD • hypertrophy • congestive heart failure • oxidative stress • ventricular fibrosis • MMP
Related Article:
Hypertension 2008 51: 28-30.
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