Loss of p47phox subunit enhances susceptibility to biomechanical stress and heart failure because of dysregulation of cortactin and actin filaments

Abstract

RATIONALE:: The classic phagocyte nicotinamide adenine dinucleotide phosphate oxidase (gp91 or Nox2) is expressed in the heart. Nox2 activation requires membrane translocation of the p47 subunit and is linked to heart failure. We hypothesized that loss of p47 subunit will result in decreased reactive oxygen species production and resistance to heart failure. OBJECTIVE:: To define the role of p47 in pressure overload-induced biomechanical stress. METHODS AND RESULTS:: Eight-week-old male p47 null (p47 knockout [KO]), Nox2 null (Nox2KO), and wild-type mice were subjected to transverse aortic constriction-induced pressure overload. Contrary to our hypothesis, p47KO mice showed markedly worsened systolic dysfunction in response to pressure overload at 5 and 9 weeks after transverse aortic constriction compared with wild-type-transverse aortic constriction mice. We found that biomechanical stress upregulated N-cadherin and β-catenin in p47KO hearts but disrupted the actin filament cytoskeleton and reduced phosphorylation of focal adhesion kinase. p47 interacts with cytosolic cortactin by coimmunoprecipitation and double immunofluorescence staining in murine and human hearts and translocated to the membrane on biomechanical stress where cortactin interacted with N-cadherin, resulting in adaptive cytoskeletal remodeling. However, p47KO hearts showed impaired interaction of cortactin with N-cadherin, resulting in loss of biomechanical stress-induced actin polymerization and cytoskeletal remodeling. In contrast, Nox2 does not interact with cortactin, and Nox2-deficient hearts were protected from pressure overload-induced adverse myocardial and intracellular cytoskeletal remodeling. CONCLUSIONS:: We showed a novel role of p47 subunit beyond and independent of nicotinamide adenine dinucleotide phosphate oxidase activity as a regulator of cortactin and adaptive cytoskeletal remodeling, leading to a paradoxically enhanced susceptibility to biomechanical stress and heart failure. © 2013 American Heart Association, Inc.