Department of Pathology and Pathophysiology, Southeast University School of Medicine, Nanjing, 210009, China.
Department of Pathology and Pathophysiology, Southeast University School of Medicine, Nanjing, 210009, China.
Free Radic Biol Med. 2019 Dec;145:175-186. doi: 10.1016/j.freeradbiomed.2019.09.015. Epub 2019 Sep 18.
The cardiovascular efficacy of glucose-lowering drugs is needed due to the cardiovascular complication in type 2 diabetes mellitus (T2DM). Acarbose is an α-glucosidase inhibitor that suppresses postprandial hyperglycemia, however, the cardiovascular protection of acarbose has still remained controversial. NLRP3 inflammasome activation mediated tight junction disruption, a hallmark event of endothelial barrier dysfunction leading to endothelial hyperpermeability in diabetes. Given the anti-inflammatory property of acarbose, it was investigated that acarbose protected against vascular endothelial barrier dysfunction through inhibiting NLRP3 inflammasome in vascular endothelial cells in T2DM rats. The rat aortic endothelial cells (RAECs) were incubated with high glucose (HG, 30 mM) for 24 h in vitro. It was found that HG significantly induced the formation and activation of NLRP3 inflammasome, which was markedly blocked by acarbose treatment. Furthermore, acarbose blocked the Nox4-dependent superoxide (O) generation, which regulated NLRP3 inflammasome in RAECs. Importantly, we found that acarbose remarkably enhanced the junction protein expression of ZO-1 and VE-Cadherin and consequently abolished vascular hyperpermeability, which was associated with inhibiting NLRP3 inflammasome in RAECs. In vivo, acarbose intervention relieved vascular leakage in the heart of diabetic rats injected with Evans blue dye and the vasodilatory response to acetylcholine, which was accompanied with the restoration of ZO-1, VE-Cadherin, Nox4 and NLRP3 inflammasome in the aortal endothelium of diabetic rats. Taken together, our data indicated that acarbose ameliorated endothelial barrier dysfunction by directly inhibiting NLRP3 inflammasome which was dependent on inhibiting Nox4 oxidase-dependent O production. These properties might carry a potential significance for acarbose in cardiovascular protection in diabetic patients.
由于 2 型糖尿病（T2DM）存在心血管并发症，因此需要降低血糖的药物来发挥心血管疗效。阿卡波糖是一种α-葡萄糖苷酶抑制剂，可抑制餐后高血糖，但阿卡波糖的心血管保护作用仍存在争议。NLRP3 炎性体激活介导紧密连接破坏，这是糖尿病内皮屏障功能障碍导致内皮通透性增加的标志性事件。鉴于阿卡波糖的抗炎特性，研究人员探讨了阿卡波糖是否通过抑制 T2DM 大鼠血管内皮细胞中的 NLRP3 炎性体来保护血管内皮屏障功能。在体外，将大鼠主动脉内皮细胞（RAEC）用高葡萄糖（HG，30mM）孵育 24 小时。结果发现，HG 显著诱导 NLRP3 炎性体的形成和激活，而阿卡波糖处理可显著阻断这一过程。此外，阿卡波糖阻断了 Nox4 依赖性超氧化物（O）生成，从而调节 RAECs 中的 NLRP3 炎性体。重要的是，我们发现阿卡波糖显著增强了 ZO-1 和 VE-Cadherin 的连接蛋白表达，从而消除了血管通透性增加，这与抑制 RAECs 中的 NLRP3 炎性体有关。在体内，阿卡波糖干预减轻了糖尿病大鼠注射伊文思蓝染料后心脏的血管渗漏，以及乙酰胆碱引起的血管舒张反应，同时恢复了糖尿病大鼠主动脉内皮中的 ZO-1、VE-Cadherin、Nox4 和 NLRP3 炎性体。总之，我们的数据表明，阿卡波糖通过直接抑制 NLRP3 炎性体来改善内皮屏障功能，而这依赖于抑制 Nox4 氧化酶依赖性 O 的产生。这些特性可能使阿卡波糖在糖尿病患者的心血管保护方面具有潜在意义。
