Loss of p47phox Subunit Enhances Susceptibility to Biomechanical Stress and Heart Failure due to Dysregulation of Cortactin and Actin Filaments

Abstract
Rationale: The classical phagocyte NADPH oxidase (gp91phox or Nox2) is expressed in the heart. Nox2 activation requires membrane translocation of the p47phox subunit and is linked to heart failure. We hypothesized that loss of p47phox subunit will result in decreased ROS production and resistance to heart failure.
Objective: To define the role of p47phox in pressure-overload induced biomechanical stress.
Methods and Results: Eight weeks old male p47phox null (p47phoxKO), Nox2 null (Nox2KO) and wildtype (WT) mice were subjected to transverse aortic constriction (TAC)-induced pressure-overload. Contrary to our hypothesis, p47phoxKO mice showed markedly worsened systolic dysfunction in response to pressure-overload at 5 weeks and 9 weeks post-TAC compared to WT-TAC mice. We found that biomechanical stress upregulated N-cadherin and β-catenin in p47phoxKO hearts but disrupted the actin filament cytoskeleton and reduced phosphorylation of FAK. p47phox interacts with cytosolic cortactin by co-immunoprecipitation and double immunofluorescence staining in murine and human hearts and translocated to the membrane upon biomechanical stress where cortactin interacted with N-cadherin resulting in adaptive cytoskeletal remodeling. However, p47phoxKO 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 p47phox subunit beyond and independent of NADPH oxidase activity, as a regulator of cortactin and adaptive cytoskeletal remodeling leading to a paradoxical enhanced susceptibility to biomechanical stress and heart failure.
- Received October 13, 2012.
- Revision received April 1, 2013.
- Accepted April 3, 2013.
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- Loss of p47phox Subunit Enhances Susceptibility to Biomechanical Stress and Heart Failure due to Dysregulation of Cortactin and Actin FilamentsVaibhav B. Patel, Zuocheng Wang, Dong Fan, Pavel Zhabyeyev, Ratnadeep Basu, Subhash K. Das, Wang Wang, Jessica L DesAulniers, Steven M. Holland, Zamaneh Kassiri and Gavin Y. OuditCirculation Research. 2013;CIRCRESAHA.112.300299, originally published April 3, 2013https://doi.org/10.1161/CIRCRESAHA.111.300299
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- Loss of p47phox Subunit Enhances Susceptibility to Biomechanical Stress and Heart Failure due to Dysregulation of Cortactin and Actin FilamentsVaibhav B. Patel, Zuocheng Wang, Dong Fan, Pavel Zhabyeyev, Ratnadeep Basu, Subhash K. Das, Wang Wang, Jessica L DesAulniers, Steven M. Holland, Zamaneh Kassiri and Gavin Y. OuditCirculation Research. 2013;CIRCRESAHA.112.300299, originally published April 3, 2013https://doi.org/10.1161/CIRCRESAHA.111.300299