Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China.
Department of Hepatic Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China.
Biochim Biophys Acta Mol Basis Dis. 2017 Jun;1863(6):1556-1567. doi: 10.1016/j.bbadis.2017.02.012. Epub 2017 Feb 13.
It has been well documented that hypoadiponectinemia is associated with impaired endothelium-dependent vasodilation. However, the exact molecular mechanism which mediates this process has not been fully described. The current study aimed to investigate the role of hypoadiponectinemia-induced NLRP3 inflammasome activation in diabetic vascular endothelial dysfunction and its molecular mechanism. Male adult adiponectin knockout mice and wild type mice were fed with a high fat diet to establish a type 2 diabetic mellitus model. In addition, human umbilical vein endothelial cells (HUVECs) were cultured and subjected to high glucose/high fat (HG/HF). The NLRP3 inflammasome activation was increased in type 2 diabetic mice and treatment of diabetic aortic segments with MCC950, a potent selective inhibitor of NLRP3 inflammasome ex vivo improved endothelial-dependent vasorelaxation. NLRP3 inflammasome activation and vascular endothelial injury were significantly increased in APN-KO mice compared with WT mice in diabetes and MCC950 decreased diabetic vascular endothelial dysfunction to comparable levels in APN-KO mice and WT mice. Adiponectin could decrease NLRP3 inflammasome activation and attenuate endothelial cell injury, which was abolished by NLRP3 inflammasome overexpression. Inhibition of peroxynitrite formation preferentially attenuated NLRP3 inflammasome activation in APN-KO diabetic mice. The current study demonstrated for the first time that hypoadiponectinemia-induced NLRP3 inflammasome activation was a novel mechanism of diabetic vascular endothelial dysfunction.
已有充分文献记载，低脂联素血症与内皮依赖性血管舒张功能障碍有关。然而，介导这一过程的确切分子机制尚未完全描述。本研究旨在探讨低脂联素血症诱导的 NLRP3 炎性小体激活在糖尿病血管内皮功能障碍及其分子机制中的作用。雄性成年脂联素敲除小鼠和野生型小鼠喂食高脂肪饮食，建立 2 型糖尿病模型。此外，培养人脐静脉内皮细胞（HUVEC）并进行高糖/高脂（HG/HF）处理。NLRP3 炎性小体激活在 2 型糖尿病小鼠中增加，用 NLRP3 炎性小体的有效选择性抑制剂 MCC950 处理糖尿病主动脉段，可改善内皮依赖性血管舒张。与 WT 小鼠相比，APN-KO 小鼠在糖尿病中 NLRP3 炎性小体激活和血管内皮损伤显著增加，MCC950 可使 APN-KO 小鼠和 WT 小鼠的糖尿病血管内皮功能障碍降低至相似水平。脂联素可降低 NLRP3 炎性小体激活并减轻内皮细胞损伤，而过表达 NLRP3 炎性小体可消除脂联素的这种作用。抑制过氧亚硝酸盐的形成可优先减轻 APN-KO 糖尿病小鼠中 NLRP3 炎性小体的激活。本研究首次证明，低脂联素血症诱导的 NLRP3 炎性小体激活是糖尿病血管内皮功能障碍的一种新机制。
