Abstract 935: Extracellular Sod Deficiency Exacerbates Pressure Overload Induced Left Ventricular Hypertrophy And Dysfunction
Extracellular SOD (SOD3) 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. SOD3 expression is decreased in the failing heart, but whether decrease of SOD3 can contribute to the development of contractile dysfunction or congestive heart failure (CHF) was not clear. To examine this question, we used transverse aortic constriction (TAC) to produce systolic overload in SOD3 gene deficient (KO) mice, and wild type (Wt) mice. SOD3 KO had no effect on left ventricular (LV) function under unstressed conditions, but resulted in a small but significant increase of myocardial fibrosis. Under unstressed conditions SOD3 KO had no effect on myocardial total SOD activity, the ratio of glutathione disulfide to glutathione (GSSG/GSH), thiobarbituric acid-reactive substances (TBARS), nitrotyrosine content or superoxide anion production. However, in response to TAC for 6 weeks, SOD3 KO mice developed more severe LV hypertrophy (heart weight increased 2.56-fold in KO mice as compared to 1.99-fold in Wt mice) and more pulmonary congestion (lung weight increased 2.92-fold in KO mice as compared to 1.84-fold in Wt mice). SOD3 KO mice also had more LV dilation and a greater reduction of LV fractional shortening and LV dP/dtmax after TAC. TAC resulted in greater increases of myocardial ANP, nitrotyrosine, TBARS, the ratio of GSSG/GSH and superoxide anion content in SOD3 KO mice as compared to Wt mice. Most interestingly, administration mitochondrial SOD mimetic M40401 significantly abolished TAC-induced ventricular oxidative stress, hypertrophy and dysfunction in Wt, while this protective effect is diminished in SOD3 KO mice, suggesting that a treatment to specifically decrease extracelluar oxidative stress may be needed to protect the hearts with a decrease of SOD3 content. The finding that SOD3 KO had no effect on myocardial total SOD activity, but significantly exacerbated chronic TAC induced ventricular oxidative stress and LV remodeling implies that the specific extracellular location of SOD3 is more important than its contribution to overall SOD activity in protecting the heart against contractile dysfunction following pressure overload.