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Oxidative stress improves coronary endothelial function through activation of the pro-survival kinase AMPK

Ehtesham Shafique1, Wing C Choy, Yuhong Liu

  • 1Cardiovascular Research Center, Division of Cardiothoracic Surgery, Department of Surgery, Rhode Island Hospital, Providence, RI 02903, USA.

Aging
|September 11, 2013
PubMed

Insights

Reactive oxygen species (ROS) may protect cardiovascular health. Increased ROS in endothelial cells improved coronary vasodilation and protected against cell death by activating the AMPK-eNOS pathway.

Area of Science:

  • Cardiovascular Physiology
  • Endothelial Biology
  • Oxidative Stress Research

Background:

  • The role of reactive oxygen species (ROS) in cardiovascular aging is debated, with clinical trials on antioxidants yielding disappointing results.
  • NADPH oxidase-derived ROS paradoxically influence endothelial function, challenging the long-held view of ROS as solely detrimental.

Purpose of the Study:

  • To investigate the impact of increased endothelial cell (EC)-specific ROS on coronary endothelial function.
  • To elucidate the signaling pathways involved in ROS-mediated endothelial protection.

Main Methods:

  • Generation of a novel Tet-ON/OFF conditional transgenic mouse (Tet-Nox2:VE-Cad-tTA) for EC-specific Nox2 (NADPH oxidase) overexpression.
  • Assessment of coronary vasodilation, EC signaling (eNOS, AMPK, CaMKKβ), and autophagy in response to increased EC-ROS.
  • Evaluation of EC survival under oxidant stress.

Main Results:

  • Endothelium-dependent coronary vasodilation was significantly enhanced in mice with increased EC-ROS (Tet-OFF Nox2) compared to controls (Tet-ON).
  • Increased ROS activated the CaMKKβ-AMPK pathway, leading to enhanced eNOS activation, nitric oxide (NO) synthesis, and AMPK-dependent vasodilation.
  • AMPK activation promoted autophagy, conferring protection against oxidant-induced EC death.

Conclusions:

  • Elevated ROS levels in endothelial cells can exert protective effects on endothelial homeostasis.
  • The AMPK-eNOS signaling axis mediates the beneficial effects of ROS on coronary vasodilation and EC survival.
  • Findings suggest a protective role for increased ROS in aging cardiovascular conditions via endothelial protection.

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