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Nox4 regulates the eNOS uncoupling process in aging endothelial cells.

Hwa-Young Lee1, Hafiz Maher Ali Zeeshan1, Hyung-Ryong Kim2

  • 1Department of Pharmacology and Institute of New Drug Development, School of Medicine, Chonbuk National University, Jeonju, Chonbuk, South Korea.

Free Radical Biology & Medicine
|September 17, 2017
PubMed
Summary

Aging endothelial cells show reduced nitric oxide (NO) and increased superoxide due to NADPH oxidase 4 (Nox4) activation. This Nox4-induced endoplasmic reticulum (ER) stress causes eNOS uncoupling, a key factor in vascular aging.

Keywords:
ER stressNONox4Superoxide anion radicaleNOS

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Area of Science:

  • Endothelial cell biology
  • Vascular aging mechanisms
  • Redox signaling

Background:

  • Reactive oxygen species (ROS) and associated signaling pathways contribute to endothelial dysfunction during vascular aging.
  • Endothelial nitric oxide synthase (eNOS) coupling status is critical for vascular aging phenotypes.

Purpose of the Study:

  • To investigate the eNOS coupled/uncoupled system signaling in aging human umbilical vein endothelial cells (HUVEC).
  • To elucidate the role of NADPH oxidase 4 (Nox4) and endoplasmic reticulum (ER) stress in eNOS uncoupling during endothelial aging.

Main Methods:

  • Culturing HUVEC and assessing changes with passage number.
  • Measuring nitric oxide (NO), superoxide anion radical (O2-), and eNOS Ser1177 levels.
  • Investigating the involvement of NADPH oxidase 4 (Nox4), protein disulfide isomerase (PDI), ER stress markers (HSP90, IRE-1α, PERK), and eNOS binding.
  • Utilizing chemical inhibitors and Nox4 siRNA approaches.

Main Results:

  • Passage number increase led to decreased NO and eNOS Ser1177, and increased O2-.
  • Aging cells exhibited heightened Nox4 and PDI activation, causing ER redox imbalance and ER stress.
  • ER stress disrupted HSP90-IRE-1α/PERK interactions, reduced HSP90 stability, and dissociated eNOS from HSP90, resulting in eNOS uncoupling.
  • Nox4 and associated ER stress were identified as major contributors to eNOS uncoupling.

Conclusions:

  • Nox4 activation and subsequent ER stress are key drivers of eNOS uncoupling in aging endothelial cells.
  • Targeting Nox4 and ER stress pathways may offer therapeutic strategies for vascular aging.