Overexpression of MnSOD reduces oxidative stress and pro‐apoptotic signaling in the aging mouse heart

Abstract

The aging heart is characterized by increased oxidative stress and cell loss via apoptosis and necrosis. Aging increases apoptotic signaling (e.g., Bax, caspase-3 cleavage), in the heart while caloric restriction and exercise retard apoptosis. The Mn isoform of superoxide dismutase (Mn-SOD) may reduce oxidative stress, ischemia-reperfusion injury, and apoptosis. We hypothesized that MnSOD overexpression using a transgenic mouse model would reduce markers of oxidative stress and apoptosis in the aging left ventricle. Hearts were extracted from young (8 mo) wild type (YWT), young MnSOD transgenic (YTg), old (28 mo) wild-type (OWT), & old MnSOD transgenic (OTg) mice. Higher MnSOD protein expression in the left ventricle was confirmed in both young YTg and OTg. Pro-apoptotic Bax and cleaved caspase-3 as well as oxidative stress marker 4-hydroxynonenal adducts (4-HNE) were measured using Western blot analysis. Total hydroperoxides were determined using the ferrous oxide-xylenol orange technique. Aging increased 4-HNE (+37%), while MnSOD overexpression reduced both 4-HNE (−36%) and total hydroperoxides (−27%) in the OTg left ventricle. Cleaved caspase-3 levels were greater (+27%) in OWT than YWT, while MnSOD overexpression reduced cleaved caspase-3 levels (−40%). In addition, Bax protein expression was 32% lower in OTg than OWT. These data indicate that MnSOD overexpression reduces oxidative stress and pro-apoptotic signaling in the aging mouse heart. Supported by Texas American Heart Association (GIA # 0555064Y)