核受体PPARδ：SGLT2抑制剂调控血管内皮功能紊乱的新机制

Vascular endothelial dysfunction is a key pathological step in atherosclerosis, hypertension and diabetes. Clinical research showed that sodium-glucose cotransporter-2 (SGLT2) inhibitors, a new group of oral medications used for treating diabetes not only improving glycaemic control but also reducing the risks of composite cardiovascular events. However, the glucose lowering-independent mechanism of SGLT2 inhibitors on vascular function is unknown. Our preliminary results showed that SGLT2 inhibitors improved the high glucose impaired endothelium-dependent relaxation (EDR) and ameliorated endothelial endoplasmic reticulum stress (ER stress). In addition, we showed that SGLT2 inhibitors activated peroxisome proliferators-activated receptor δ (PPARδ) activity in endothelial cells (ECs). In addition, these vasoprotective effects of SGLT2 inhibitors were attenuated by PPARδ antagonist. Thus, the central hypothesis is that SGLT2 inhibitors ameliorated endothelial dysfunction in diabetes through the inhibition of ER stress and PPARδ-mediated mechanisms. We will examine this hypothesis by addressing the following specific aims: 1) To examine the effects and mechanisms of SGLT2 inhibitors on PPARδ activation. 2) To examine the roles of PPARδ in regulation of endoplasmic reticulum stress by SGLT2 inhibitors. 3) To characterize the role of SGLT2 inhibitors in the regulation of ER stress and vasoprotective effect in diabetes-related vascular injury. These studies should help elucidating the new metabolic regulation mechanism of vascular homeostasis and remodeling and developing novel therapeutics against diabetes and other vascular diseases.

血管内皮功能紊乱是动脉粥样硬化、高血压等多种重大心血管疾病以及糖尿病等重大代谢疾病血管并发症的关键病理环节。临床研究表明：新型降糖药SGLT2抑制剂显著改善糖尿病患者心血管预后。然而，其心血管保护机制亟待研究。我们发现：SGLT2抑制剂改善内皮依赖的血管舒张并抑制内质网应激。此外，SGLT2抑制剂激活核受体PPARδ。而且，PPARδ拮抗剂阻断SGLT2抑制剂的保护作用。由此，我们推测：核受体PPARδ的激活可能是SGLT2抑制剂调控内质网应激及血管保护功能的新机制。围绕这一假说，拟开展以下工作：1）解析SGLT2抑制剂对PPARδ的调控及PPARδ抑制内质网应激的机制；2）阐明PPARδ介导SGLT2抑制剂调控内质网应激及血管保护功能的作用；3）整体水平验证SGLT2抑制剂对糖尿病血管损伤的保护作用及分子机制。以期阐明血管稳态及重构的代谢调控新机制，为代谢相关血管疾病的防治提供新的策略。

血管内皮功能紊乱是动脉粥样硬化、高血压等多种重大心血管疾病以及糖尿病等重大代谢疾病血管并发症的关键病理环节。糖尿病血管并发症（冠心病、脑血管疾病、周围血管疾病等、肾病、视网膜病和神经病变等）是糖尿病患者致死、致残的主要原因。新型口服降糖药物钠-葡萄糖共转运蛋白2 （Sodium-glucose cotransporter-2, SGLT2）如卡格列净、恩格列净、达格列净等通过抑制肾脏近曲小管对葡萄糖的重吸收而发挥降糖作用。临床试验证实SGLT2抑制剂有显著的心血管获益，其心血管保护机制亟待研究。核受体PPARδ是血管稳态的关键调控因子，也是心血管疾病干预的潜在靶点。本项目主要研究了SGLT2抑制剂及核受体PPARδ改善血管内皮功能的机制。取得的主要成果包括：1）阐明了PPARδ天然配体抑制内皮细胞内质网应激、改善血管内皮舒张功能障碍的作用及机制；2）发现了卡格列净及恩格列净在体给药及离体处理均能以PPARδ依赖的方式有效改善内皮依赖的血管舒张功能、降低血管内皮内质网应激分子标志；3）研究了卡格列净及恩格列在内皮细胞诱导血红素加氧酶1（HO-1）表达的机制。HO-1作为具有抗炎及舒张血管作用的重要血管保护因子，可能参与了SGLT2抑制剂的心血管获益机制。以上结果阐明了SGLT2抑制剂改善糖尿病血管内皮功能紊乱的分子机制，并揭示糖代谢紊乱状态下血管稳态失衡的关键分子通路及干预靶点。共发表标注该项目SCI论文3篇；指导博士生5名、硕士生8名。其中毕业博士生1名、硕士生2名。