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Original Research

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

Vaibhav B. Patel, Zuocheng Wang, Dong Fan, Pavel Zhabyeyev, Ratnadeep Basu, Subhash K. Das, Wang Wang, Jessica L DesAulniers, Steven M. Holland, Zamaneh Kassiri, Gavin Y. Oudit
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https://doi.org/10.1161/CIRCRESAHA.111.300299
Circulation Research. 2013;CIRCRESAHA.112.300299
Originally published April 3, 2013
Vaibhav B. Patel
Medicine, University of Alberta, 116 ST 85 Ave University of Alberta, 407-HMRC, Edmonton, N/A, T6G 2S2, CANADA
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Zuocheng Wang
University of Alberta, 407, Heritage Medical Research Centre, Edmonton, T6G 2R3, CANADA
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Dong Fan
University of Alberta, 116 street 85 avenue, 474 HMRC University of Alberta, Edmonton, N/A, T6G2S2, CANADA
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Pavel Zhabyeyev
University of Alberta, Heritage Medical Research Building, Rm 460, Edmonton, N/A, CANADA
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Ratnadeep Basu
Physiology, University of Alberta, 474, HMRC, Edmonton, N/A, T6G 2S2, CANADA
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Subhash K. Das
Medicine, University of Alberta, University of Albrta,HMRC,Room#407,116ST,85Ave, Edmonton, N/A, T6G 2S2, CANADA
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Wang Wang
University of Alberta, 87AV 112 street, HMRC 407, Edmonton, N/A, T6G 2S2, CANADA
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Jessica L DesAulniers
Medicine, University of Alberta, 116 St & 85 Ave, 407 HMRC, Edmonton, N/A, T6G 2S2, CANADA
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Steven M. Holland
LCID, National Institute of Allergy and Infectious Diseases, CRC B3-4141, MSC 1684, Bethesda, Maryland, 20892-1684, UNITED STATES
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Zamaneh Kassiri
Department of Physiology, University of Alberta, 474 HMRC, Edmonton, Alberta, N/A, T6G 2S2, CANADA
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Gavin Y. Oudit
Department of Medicine, University of Alberta, Division of Cardiology, Mazankowski Alberta Heart Institute, Alberta, N/A, T6G 2S2, CANADA
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  • For correspondence: gavin.oudit@ualberta.ca
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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.

  • p47phox
  • pressure overload
  • mechanotransduction
  • heart failure
  • remodeling
  • 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 Filaments
    Vaibhav 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. Oudit
    Circulation Research. 2013;CIRCRESAHA.112.300299, originally published April 3, 2013
    https://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 Filaments
    Vaibhav 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. Oudit
    Circulation Research. 2013;CIRCRESAHA.112.300299, originally published April 3, 2013
    https://doi.org/10.1161/CIRCRESAHA.111.300299
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