Integrative Physiology The I B Kinase /Nuclear Factor B Signaling Pathway Protects the Heart From Hemodynamic Stress Mediated by the Regulation of Manganese Superoxide Dismutase Expression

Cardiomyocyte death plays an important role in the pathogenesis of heart failure. The nuclear factor (NF)B signaling pathway regulates cell death, however, the effect of NFB pathway on cell death can vary in different cells or stimuli. The purpose of the present study was to clarify the in vivo role of the NFB pathway in response to pressure overload. First, we subjected C57Bl6/J mice to pressure overload by means of transverse aortic constriction (TAC) and examined the activity of the NFB pathway in response to pressure overload. I B kinase (IKK) and NFB were activated after TAC. Then, we investigated the role of the activation using cardiac-specific IKK -deficient mice (CKO). CKO displayed normal global cardiac structure and function compared with control littermates. We subjected CKO and control mice to pressure overload. One week after TAC, CKO showed cardiac dilation, dysfunction, and lung congestion, which are characteristics of heart failure. The number of apoptotic cells in the hearts of CKO mice increased significantly after TAC. The levels of manganese superoxide dismutase mRNA and protein expression in CKO after TAC were significantly attenuated compared with control mice. The levels of oxidative stress and c-Jun N-terminal kinase (JNK) activation in CKO after TAC were significantly greater than those in control mice. Isoproterenol-induced cell death of isolated adult CKO cardiomyocytes was inhibited by treatment with either a manganese superoxide dismutase mimetic or a JNK inhibitor. Thus, the IKK /NFB signaling pathway plays a protective role in cardiomyocytes because of the attenuation of oxidative stress and JNK activation in a setting of acute pressure overload. (Circ Res. 2009; 105:70-79.)