| First Author | Zhang Y | Year | 2023 |
| Journal | Redox Biol | Volume | 68 |
| Pages | 102944 | PubMed ID | 37890359 |
| Mgi Jnum | J:342396 | Mgi Id | MGI:7547911 |
| Doi | 10.1016/j.redox.2023.102944 | Citation | Zhang Y, et al. (2023) Nogo-B mediates endothelial oxidative stress and inflammation to promote coronary atherosclerosis in pressure-overloaded mouse hearts. Redox Biol 68:102944 |
| abstractText | 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-alpha, IL-1beta), 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 Ca(2+) 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. |
