Abstract 1589: Cardiac-Specific Overexpression of Catalase Attenuates Pathological Remodeling in Mice with Chronic Pressure Overload
Although reactive oxygen species are increased in failing myocardium, their role in mediating pathological myocardial remodeling in vivo remains to be elucidated. We assessed the hypothesis that hydrogen peroxide mediates pressure overload-induced myocardial failure. 10-week old male mice with cardiac-specific overexpression of catalase (CAT) and age-matched male wild-type (WT) mice were subjected to ascending aortic constriction (AAC) or sham operation. Left ventricular (LV) dimensions and function were examined by serial echocardiography. At 12 weeks after AAC, we performed exercise testing on a motorized treadmill and assessed myocardial oxidative stress by immunohistochemistry for 4-hydroxy-2-nonenal expression, myocyte cross-sectional area by hematoxyline and eosin staining, myocyte apoptosis by triple staining with TUNEL, Hoechst 33258 and α-sarcomeric actin antibody, and myocardial fibrosis by Masson trichrome staining. WT AAC mice exhibited a progressive increase in LV end-diastolic dimension accompanied by a decrease in LV fractional shortening, an increase in posterior wall thickness and a 12-wk mortality of 55%. Exercise capacity was 347±19 meters in WT sham mice and reduced to 139±33 meters in WT AAC mice (P<0.05 vs. WT sham). Myocardial 4-hydroxy-2-nonenal, myocyte cross-sectional area, myocyte apoptosis and fibrosis were markedly increased in WT AAC mice compared with WT sham mice (Table⇓). In contrast, CAT AAC mice had decreased 4-hydroxy-2-nonenal, myocyte size, myocyte apoptosis and fibrosis, less LV dilation, hypertrophy and dysfunction, reduced mortality (25%), and improved exercise capacity (230±27 meters in CAT AAC, P<0.05 vs. WT AAC). Oxidative stress, mediated at least in part via hydrogen peroxide, plays an important role in mediating progressive myocardial remodeling and failure with hemodynamic overload.