Nyandwi Jean Baptiste, Ko Young Shin, Jin Hana, Yun Seung Pil, Park Sang Won, Kim Hye Jung
Department of Pharmacology, College of Medicine, Institute of Health Sciences, Gyeongsang National University, Jinju 52727, Republic of Korea; Department of Convergence Medical Science, Gyeongsang National University, Jinju 52727, Republic of Korea; Department of Pharmacy, School of Medicine and Pharmacy, College of Medicine and Health Sciences, University of Rwanda, Kigali 4285, Rwanda.
Department of Pharmacology, College of Medicine, Institute of Health Sciences, Gyeongsang National University, Jinju 52727, Republic of Korea.
Biochem Pharmacol. 2020 Dec;182:114246. doi: 10.1016/j.bcp.2020.114246. Epub 2020 Oct 2.
Elevated glucose levels in diabetes mellitus is associated with increased oxidized low density lipoprotein (oxLDL). High glucose (HG) and oxLDL are key inducers of oxidative stress and inflammatory processes responsible for diabetic vascular disorders. Rosmarinic acid is a polyphenol with antioxidant, anti-inflammatory and insulin-sensitizing effects. However, whether rosmarinic acid protects against diabetic atherosclerosis remains unknown. In this study, we aimed to investigate the protective effect of rosmarinic acid against diabetic atherosclerosis and the related signaling pathway. oxLDL-mediated oxidative stress upregulated thioredoxin-interacting protein (TXNIP) and subsequently induced binding of TXNIP to NLRP3 to mediate NLRP3 inflammasome assembly and activation under HG conditions in ECs. Reactive oxygen species (ROS) scavengers, p38 and FOXO1 inhibitors and TXNIP siRNA inhibited TXNIP protein upregulation and NLRP3 inflammasome assembly and activation. Rosmarinic acid abrogated TXNIP protein upregulation and the interaction between TXNIP and NLRP3 to attenuate NLRP3 inflammasome assembly and activation and eventually IL-1β secretion in ECs through downregulating ROS production, p38 phosphorylation and FOXO1 protein induction in ECs. These findings show that rosmarinic acid inhibits endothelial dysfunction which is shown in diabetic atherosclerosis through downregulating the p38-FOXO1-TXNIP pathway and inhibiting inflammasome activation.
糖尿病患者体内升高的葡萄糖水平与氧化型低密度脂蛋白（oxLDL）增加有关。高血糖（HG）和oxLDL是导致糖尿病血管病变的氧化应激和炎症过程的关键诱导因素。迷迭香酸是一种具有抗氧化、抗炎和胰岛素增敏作用的多酚。然而，迷迭香酸是否能预防糖尿病动脉粥样硬化尚不清楚。在本研究中，我们旨在探讨迷迭香酸对糖尿病动脉粥样硬化的保护作用及其相关信号通路。在HG条件下，oxLDL介导的氧化应激上调硫氧还蛋白相互作用蛋白（TXNIP），随后诱导TXNIP与NLRP3结合，介导内皮细胞中NLRP3炎性小体的组装和激活。活性氧（ROS）清除剂、p38和FOXO1抑制剂以及TXNIP siRNA抑制TXNIP蛋白上调以及NLRP3炎性小体的组装和激活。迷迭香酸通过下调内皮细胞中的ROS产生、p38磷酸化和FOXO1蛋白诱导，消除TXNIP蛋白上调以及TXNIP与NLRP3之间的相互作用，从而减弱NLRP3炎性小体的组装和激活，并最终减少内皮细胞中白细胞介素-1β的分泌。这些发现表明，迷迭香酸通过下调p38-FOXO1-TXNIP途径并抑制炎性小体激活，抑制糖尿病动脉粥样硬化中出现的内皮功能障碍。
