Cardiac-specific overexpression of catalase attenuates lipopolysaccharide-induced myocardial contractile dysfunction: Role of autophagy

• Published in: Free radical biology & medicine Vol. 53; no. 6; pp. 1327 - 1338
• Main Authors: Turdi, Subat, Han, Xuefeng, Huff, Anna F., Roe, Nathan D., Hu, Nan, Gao, Feng, Ren, Jun
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 15.09.2012
• Subjects: acetylcysteine; antioxidants; apoptosis; Autophagy; Cardiac; cardiac output; cardiomyocytes; caspase-3; catalase; Contractile function; echocardiography; electron microscopy; fluorescence microscopy; Free radicals; genetically modified organisms; Gram-negative bacteria; Lipopolysaccharide; lipopolysaccharides; mice; mortality; Oxidative stress; reactive oxygen species; tumor necrosis factor-alpha; Western blotting; Lipopolysaccharide; Oxidative stress; Free radicals; Autophagy; Cardiac; Contractile function
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2012.07.084

Lipopolysaccharide (LPS) from gram-negative bacteria is a major initiator of sepsis, leading to cardiovascular collapse. Accumulating evidence has indicated a role of reactive oxygen species (ROS) in cardiovascular complications in sepsis. This study was designed to examine the effect of cardiac-specific overexpression of catalase in LPS-induced cardiac contractile dysfunction and the underlying mechanism(s) with a focus on autophagy. Catalase transgenic and wild-type FVB mice were challenged with LPS (6mg/kg) and cardiac function was evaluated. Levels of oxidative stress, autophagy, apoptosis, and protein damage were examined using fluorescence microscopy, Western blot, TUNEL assay, caspase-3 activity, and carbonyl formation. A Kaplan–Meier curve was constructed for survival after LPS treatment. Our results revealed a lower mortality in catalase mice compared with FVB mice after LPS challenge. LPS injection led to depressed cardiac contractile capacity as evidenced by echocardiography and cardiomyocyte contractile function, the effect of which was ablated by catalase overexpression. LPS treatment induced elevated TNF-α level, autophagy, apoptosis (TUNEL, caspase-3 activation, cleaved caspase-3), production of ROS and O2−, and protein carbonyl formation, the effects of which were significantly attenuated by catalase overexpression. Electron microscopy revealed focal myocardial damage characterized by mitochondrial injury after LPS treatment, which was less severe in catalase mice. Interestingly, LPS-induced cardiomyocyte contractile dysfunction was prevented by the antioxidant N-acetylcysteine and the autophagy inhibitor 3-methyladenine. Taken together, our data revealed that catalase protects against LPS-induced cardiac dysfunction and mortality, which may be associated with inhibition of oxidative stress and autophagy. [Display omitted] ► We examined the effect of catalase on LPS-induced cardiac dysfunction. ► Catalase rescues LPS-induced cardiac dysfunction and remodeling. ► The beneficial effect of catalase is related to inhibition of oxidative stress.