Protective effects of acarbose against vascular endothelial dysfunction through inhibiting Nox4/NLRP3 inflammasome pathway in diabetic rats
Protective effects of acarbose against vascular endothelial dysfunction through inhibiting Nox4/NLRP3 inflammasome pathway in diabetic rats
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DOI：
10.1016/j.freeradbiomed.2019.09.015
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发表时间：
2019-12-01
影响因子：
7.4
通讯作者：
Huang, Pei-Lin
中科院分区：
文献类型：
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作者：
Li, Xiao-Xue;Ling, Sun-Kai;Huang, Pei-Lin
2型糖尿病（T2 DM）心血管并发症的发生，需要降糖药物的心血管疗效。阿卡波糖是一种α-葡萄糖苷酶抑制剂，可抑制餐后高血糖，但其心血管保护作用仍存在争议。NLRP 3炎性体活化介导紧密连接破坏，这是导致糖尿病中内皮通透性过高的内皮屏障功能障碍的标志性事件。考虑到阿卡波糖的抗炎性质，研究了阿卡波糖通过抑制T2 DM大鼠血管内皮细胞中的NLRP 3炎性体来防止血管内皮屏障功能障碍。体外培养大鼠主动脉内皮细胞（RAECs），高糖（HG，30 mM）孵育24 h。结果发现，HG显著诱导NLRP 3炎性体的形成和激活，阿卡波糖处理显著阻断。此外，阿卡波糖阻断了Nox 4依赖的超氧化物（O-2（中心点-））的产生，其调节RAEC中的NLRP 3炎性体。重要的是，我们发现阿卡波糖显著增强ZO-1和VE-钙粘蛋白的连接蛋白表达，从而消除血管通透性过高，这与抑制RAEC中的NLRP 3炎性体有关。在体实验中，阿卡波糖干预可减轻伊文思蓝引起的糖尿病大鼠心脏血管渗漏和乙酰胆碱引起的血管舒张反应，并可恢复糖尿病大鼠血管内皮ZO-1、VE-Cadherin、Nox 4和NLRP 3炎性小体的表达。综上所述，我们的数据表明阿卡波糖通过直接抑制NLRP 3炎性体来改善内皮屏障功能障碍，NLRP 3炎性体依赖于抑制Nox 4氧化酶依赖性O-2（中心点-）的产生。这些性质可能对阿卡波糖在糖尿病患者心血管保护中具有潜在的意义。
The cardiovascular efficacy of glucose-lowering drugs is needed due to the cardiovascular complication in type 2 diabetes mellitus (T2DM). Acarbose is an alpha-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 24h 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-2(center dot-)) 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-2(center dot-) production. These properties might carry a potential significance for acarbose in cardiovascular protection in diabetic patients.