Loss of NOX 2 (gp91phox) prevents oxidative stress and progression to advanced heart failure

Oxidative stress plays a key pathogenic role in experimental and human heart failure. However, the source of the reactive oxygen species is a key determinant of the cardiac adaptation to pathological stressors. Human dilated cardiomyopathy is associated with increased NOX2 levels, increased oxidative stress with adverse myocardial remodeling, and activation of the mitogen-activated protein kinase. Advanced heart failure in mice was also associated with increased NOX2 levels. We 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 increased oxidative stress, development of cardiomyocyte hypertrophy, myocardial fibrosis and increased myocardial matrix metalloproteinase activity, in response to pressure-overload. Consistent with these findings, expression of disease markers revealed marked suppression of atrial natriuretic factor, beta-myosin heavy chain, B-type natriuretic peptide and alpha-skeletal actin expression in NOX2 pressure-overloaded hearts. Activation of mitogen-activated protein kinase signaling, a well-known mediator of pathological remodeling, was lowered in the NOX2 knockout hearts in response to pressure-overload. Functional assessment using transthoracic echocardiography and invasive pressure-volume loop analysis showed a marked protection in diastolic and sy...
Source: Clinical Science - Category: Biomedical Science Authors: Source Type: research