【論文摘要】Endoplasmic Reticulum Protein Thioredoxin Domain Containing 5 Contributes to Endothelial Dysfunction and Atherosclerosis by Destabilizing Endothelial Nitric Oxide Synthase

Shih-Hsin Cheng ； Chih-Fan Yeh ； Yun Fang ； Kai-Chien Yang

《海峽循環醫學雜誌》 1卷2S期 (2019/09) Pp. 158-159

https://doi.org/10.6907/SCJ.201909/SP_1(2).0131

摘要

Background/Synopsis: Atherosclerosis is a progressive inflammatory disease characterized by accumulation of lipids in the arterial intima and build-up of atherosclerotic plaques. Interestingly, atherosclerotic lesions preferentially develop at the sites of curvature, branching and bifurcation, the areas under abnormal hemodynamics in the arteries. Exploiting RNA sequencing data obtained from human aortic endothelial cells (HAEC) stimulated with atherogenic disturbed flow, we identified thioredoxin domain containing 5 (TXNDC5), an endoplasmic reticulum protein with the enzyme activity of a protein disulfide isomerase, as a potentially important mediator of endothelial dysfunction and atherosclerosis. Objectives/Purpose: To determine the role of TXNDC5 in endothelial dysfunction and atherosclerosis Methods/Results: TXNDC5 expression was significantly upregulated in HAEC exposed to disturbed flow, as well as in the human aortic atherosclerotic lesions. Endothelial TXNDC5 level was markedly upregulated in the common carotid arteries (CCA) from Apoe-/- mice after partial carotid artery ligation (PCAL), a well-described method to generate disturbed flow in CCA, as well as from Apoe-/- mice fed with 12-week high fat diet (HFD). The upregulation of endothelial TXNDC5 was accompanied by downregulation of endothelial nitric oxide synthase (eNOS) and heat shock protein 90 (HSP90), two atheroprotective factors in endothelial cells. A cycloheximide protein chase assay revealed decelerated degradation of eNOS in HAEC with TXNDC5 knockdown. Furthermore, administration of HSP90 inhibitor, geldanamycin, reversed TXNDC5 deficiency-induced upregulation of eNOS in HAEC. Importantly, Apoe-/- x Txndc5-/-, compared with Apoe-/-, mice showed significantly reduced aortic atherosclerotic lesion areas after HFD treatment. Similarly, targeted deletion of Txndc5 prevented exacerbation of atheroma and eNOS downregulation resulted from PCAL in CCA in Apoe-/- mice fed with HFD. In addition, the atheroprotective effects of Txndc5 deficiency were diminished after treatment with L-NAME, an eNOS inhibitor. These data strongly suggest that TXNDC5 promotes endothelial dysfunction and atherosclerosis by destabilizing eNOS. Moreover, endothelium-specific knockout of Txndc5 (Tie2-Cre/ERT2 x Txndc5fl/fl) in Apoe-/- mice also showed significantly attenuated atherosclerotic lesion caused by PCAL, demonstrating the atherogenic role of TXNDC5 specifically in the endothelium. Taken together, the results from these experiments suggest an essential role of TXNDC5 in disturbed flow/dyslipidemia-induced endothelial dysfunction and atherosclerosis through eNOS regulation. Conclusion: The present study revealed a previously undiscovered role of ER protein TXNDC5 in modulating endothelial function in response to atherogenic stimuli by post-transcriptional regulation of eNOS. Targeted deletion of Txndc5 protects against endothelial dysfunction and atherosclerosis in Apoe-/- mice through stabilizing eNOS. Targeting TXNDC5, therefore, could be a novel therapeutic approach to treat or prevent atherosclerotic cardiovascular diseases.