Oxidative stress plays a key pathogenic role in experimental and human heart failure. However, the source of ROS (reactive oxygen species) is a key determinant of the cardiac adaptation to pathological stressors. In the present study, we have shown that human dilated cardiomyopathy is associated with increased NOX2 (NADPH oxidase 2) levels, increased oxidative stress with adverse myocardial remodelling and activation of MAPKs (mitogen-activated protein kinases). Advanced heart failure in mice was also associated with increased NOX2 levels. Furthermore, we have utilized the pressure-overload model to examine the role of NOX2 in advanced heart failure. Increased cardiomyocyte hypertrophy and myocardial fibrosis in response to pressure overload correlated with increased oxidative stress, and loss of NOX2 prevented the increase in oxidative stress, development of cardiomyocyte hypertrophy, myocardial fibrosis and increased myocardial MMP (matrix metalloproteinase) activity in response to pressure overload. Consistent with these findings, expression of disease markers revealed a marked suppression of atrial natriuretic factor, β-myosin heavy chain, B-type natriuretic peptide and α-skeletal actin expression in pressure-overloaded hearts from NOX2-deficient mice. Activation of MAPK signalling, a well-known mediator of pathological remodelling, was lowered in hearts from NOX2-deficient mice in response to pressure overload. Functional assessment using transthoracic echocardiography and invasive pressure–volume loop analysis showed a marked protection in diastolic and systolic dysfunction in pressure-overloaded hearts from NOX2-deficient mice. Loss of NOX2 prevented oxidative stress in heart disease and resulted in sustained protection from the progression to advanced heart failure. Our results support a key pathogenic role of NOX2 in murine and human heart failure, and specific therapy antagonizing NOX2 activity may have therapeutic effects in advanced heart failure.
Loss of NOX2 (gp91phox) prevents oxidative stress and progression to advanced heart failure
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Nirmal Parajuli, Vaibhav B. Patel, Wang Wang, Ratnadeep Basu, Gavin Y. Oudit; Loss of NOX2 (gp91phox) prevents oxidative stress and progression to advanced heart failure. Clin Sci (Lond) 1 September 2014; 127 (5): 331–340. doi: https://doi.org/10.1042/CS20130787
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