Nogo-B mediates endothelial oxidative stress and inflammation to promote coronary atherosclerosis in pressure-overloaded mouse hearts

Redox Biol. 2023 Dec:68:102944. doi: 10.1016/j.redox.2023.102944. Epub 2023 Oct 21.

Abstract

Aims: Endothelial dysfunction plays a pivotal role in atherosclerosis, but the detailed mechanism remains incomplete understood. Nogo-B is an endoplasmic reticulum (ER)-localized protein mediating ER-mitochondrial morphology. We previously showed endothelial Nogo-B as a key regulator of endothelial function in the setting of hypertension. Here, we aim to further assess the role of Nogo-B in coronary atherosclerosis in ApoE-/- mice with pressure overload.

Methods and results: We generated double knockout (DKO) mouse models of systemically or endothelium-specifically excising Nogo-A/B gene on an ApoE-/- background. After 7 weeks of transverse aortic constriction (TAC) surgery, compared to ApoE-/- mice DKO mice were resistant to the development of coronary atherosclerotic lesions and plaque rapture. Sustained elevation of Nogo-B and adhesion molecules (VCAM-1/ICAM-1), early markers of atherosclerosis, was identified in heart tissues and endothelial cells (ECs) isolated from TAC ApoE-/- mice, changes that were significantly repressed by Nogo-B deficiency. In cultured human umbilical vein endothelial cells (HUVECs) exposure to inflammatory cytokines (TNF-α, IL-1β), Nogo-B was upregulated and activated reactive oxide species (ROS)-p38-p65 signaling axis. Mitofusin 2 (Mfn2) is a key protein tethering ER to mitochondria in ECs, and we showed that Nogo-B expression positively correlated with Mfn2 protein level. And Nogo-B deletion in ECs or in ApoE-/- mice reduced Mfn2 protein content and increased ER-mitochondria distance, reduced ER-mitochondrial Ca2+ transport and mitochondrial ROS generation, and prevented VCAM-1/ICAM-1 upregulation and EC dysfunction, eventually restrained atherosclerotic lesions development.

Conclusion: Our study revealed that Nogo-B is a critical modulator in promoting endothelial dysfunction and consequent pathogenesis of coronary atherosclerosis in pressure overloaded hearts of ApoE-/- mice. Nogo-B may hold the promise to be a common therapeutic target in the setting of hypertension.

Keywords: Coronary atherosclerosis; Mitochondria; Nogo-B; Pressure overload; Reactive oxygen species.

MeSH terms

  • Animals
  • Apolipoproteins E / genetics
  • Atherosclerosis* / genetics
  • Atherosclerosis* / metabolism
  • Coronary Artery Disease* / genetics
  • Coronary Artery Disease* / metabolism
  • Endothelium / metabolism
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Humans
  • Hypertension* / metabolism
  • Inflammation / metabolism
  • Intercellular Adhesion Molecule-1 / genetics
  • Intercellular Adhesion Molecule-1 / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nogo Proteins / genetics
  • Nogo Proteins / metabolism
  • Oxidative Stress
  • Plaque, Atherosclerotic* / metabolism
  • Reactive Oxygen Species / metabolism
  • Vascular Cell Adhesion Molecule-1 / genetics
  • Vascular Cell Adhesion Molecule-1 / metabolism

Substances

  • Intercellular Adhesion Molecule-1
  • Reactive Oxygen Species
  • Vascular Cell Adhesion Molecule-1
  • Nogo Proteins
  • Apolipoproteins E