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  • In the vasculature the interaction


    In the vasculature, the interaction of VE-cadherin and β‑catenin at endothelial cell-cell junctions controls vascular integrity [33]. However, OxLDL induces the activation of β‑catenin in human aortic smooth muscle cells, and the active β‑catenin associates with TCF4 and translocates into the nucleus, thus playing an important role in atherosclerosis [12]. Despite research on the interaction between eNOS and β‑catenin in endothelial cells, the role of eNOS S-nitrosylation in regulating the eNOS/β‑catenin complex and the subsequent signaling pathway in the context of endothelial dysfunction is not clearly defined [16]. Hence, we examined the involvement of eNOS S-nitrosylation in β‑catenin signaling using a NOS inhibitor and mutations of eNOS. L-NAME, a dual NOS inhibitor, not only diminished eNOS S-nitrosylation (Fig. 3) but also inhibited the binding of β‑catenin to eNOS induced by OxLDL in endothelial Omadacycline price (Fig. 4). Furthermore, the interaction of β‑catenin and eNOS, nuclear translocation and transcriptional activity of β‑catenin were decreased in eNOS mutation (C94S and C99S)-transfected endothelial cells (Fig. 4). Together, our study suggested for the first time that the increased interaction of eNOS and β‑catenin induced by OxLDL is dependent on the S-nitrosylation of eNOS. OxLDL down-regulates eNOS and up-regulates iNOS, thereby augmenting the formation of NO and protein S-nitrosylation in human endothelial cells [26]. Importantly, iNOS-mediated S-nitrosylation plays an increasingly significant role in cardiovascular diseases [34]. For example, iNOS-mediated IRE1α S-nitrosylation links obesity-associated inflammation to endoplasmic reticulum dysfunction [34]. Additionally, S-nitrosylation of TSC2 by iNOS-derived NO is associated with impaired TSC2/TSC1 dimerization, mTOR pathway activation, and proliferation of human melanoma [35]. Recent studies have discovered that innate immunity is necessary for the transdifferentiation of fibroblasts to endothelial cells. Innate immune activation increases the iNOS generation of NO to S-nitrosylate RING1A, thus releasing epigenetic repression to achieve effective transdifferentiation [36]. We also confirmed that OxLDL significantly increased iNOS expression and NO release in endothelial cells (Fig. 5 and Suppl. Fig. 3), but without change in GSNOR and Trx expression (Suppl. Fig. 4). To explore whether eNOS S-nitrosylation induced by OxLDL was ascribed to iNOS-derived NO, 1400 W, which is a specific inhibitor of iNOS, was used in our study. As our results demonstrated, the iNOS inhibitor suppressed OxLDL-induced eNOS S-nitrosylation, cell migration and adhesion molecule expression (Fig. 5). Mechanistically, the iNOS inhibitor also reduced the association and nuclear translocation of eNOS and β‑catenin in OxLDL-treated endothelial cells (Fig. 6). These results suggested that iNOS activation contributes to OxLDL-induced eNOS S-nitrosylation and endothelial dysfunction. In conclusion, this study provides evidence that OxLDL increases iNOS-mediated S-nitrosylation of eNOS at Cys94 and Cys99 to regulate the interaction of eNOS and β‑catenin to induce endothelial dysfunction (Fig. 7). These data highlight a novel insight into the mechanism of atherosclerosis. The following are the supplementary data related to this article.
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    Introduction The vascular endothelium is a single layer of cells adjacent to the lumen of blood vessels and plays an important physiological role in vascular homeostasis including maintenance of blood fluidity, regulation of vascular tone, modulation of pro-inflammatory molecule production, pro-inflammatory immune responses, and neovascularization [1]. Risk factors such as obesity, insulin resistance, diabetes, smoking, and aging can induce alterations in endothelium morphology and endothelium dysfunction, which contribute to arterial stiffness, atherosclerosis, hypertension, stroke, and coronary artery disease [1]. In this regard, increasing aging in our population is a major risk factor and represents a major global health challenge in the pathogenesis of cardiovascular disease (CVD) [2]. Vascular cellular senescence is a process in which vascular cells cease dividing and undergo distinctive phenotypic changes such as profound chromatin and secretome alterations and tumor-suppressor activation [3]. The senescence of vascular endothelial cells (ECs) has been found to play a key role in vascular aging leading to the initiation, progress, and advancement of CVD [2]. Aged ECs usually become flatter and enlarged with an increasingly polypoid nucleus. These changes are accompanied by modulation in cytoskeleton integrity, angiogenesis, proliferation, and cell migration [4]. For instance, senescent ECs show attenuated endothelial nitric oxide (NO) production, increased endothelin-1 (ET-1) release, elevated inflammation and cell apoptosis [4]. Thus, EC senescence induces vascular structural and functional changes enhance thrombosis, inflammation, and atherosclerosis with impairment of vessel tone, angiogenesis, and vascular integrity, all of which contribute to development and progression of CVD [1]. For example, in a large randomized controlled sub-study of the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) involving 541 men or women aged 70 to 82 years it was found that elevated levels of plasminogen activator and Von Willebrand factor, as markers of EC injury and dysfunction, were associated with lower cerebral blood flow in older adults at high risk for CVD [5]. Atorvastatin for Reduction of Myocardial Damage during Angioplasty- Acute Coronary Syndromes (ARMYDA-ACS) trial suggested that endothelial progenitor cells (EPCs) may promote endogenous vascular repair and contribute to cardio-protection and reduction of CVD morbidity and mortality [6]. However, the molecular mechanisms of EC senescence and the linkage to the underlying pathophysiological changes are not yet completely understood. In this review, we discuss the roles and mechanisms of EC senescence in the process of vascular aging and CVD.