Regulation of NLRP3 inflammasome by CD38 through cADPR-mediated Ca2+ release in vascular smooth muscle cells in diabetic mice
Regulation of NLRP3 inflammasome by CD38 through cADPR-mediated Ca2+ release in vascular smooth muscle cells in diabetic mice
复制标题
CD38 通过 cADPR 介导的糖尿病小鼠血管平滑肌细胞中 Ca(2) 释放来调节 NLRP3 炎症小体。
DOI：
10.1016/j.lfs.2020.117758
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发表时间：
2020-08-15
期刊：
影响因子：
6.1
通讯作者：
Xu, Ming
中科院分区：
文献类型：
--
作者：
Li, Jia-Peng;Wei, Wei;Xu, Ming
目的：NLR家族pyrin domain containing 3（NLRP 3）炎性小体激活有助于糖尿病心血管并发症的发展。在血管平滑肌细胞（VSMC）中，CD 38通过环ADP-核糖（cADPR）介导的Ca 2+信号调节血管炎症。Ca 2+动员可能通过影响线粒体功能来调节炎性小体激活。然而，目前还不清楚是否CD 38调节NLRP 3炎症激活VSMCs通过cADPR依赖的Ca 2+释放在diabeticcondition.Main方法和关键发现：在VSMCs中，我们观察到，高糖（HG，30 mM）增强CD 38蛋白表达和ADP核糖环化酶活性。此外，沿着NLRP 3、胰岛细胞增殖相关斑点样蛋白CARD（ASC）及其共定位的减少，CD 38基因缺陷可显著抑制VSMCs中活性caspase 1（p20）和IL-1 β的表达。此外，CD 38调节细胞内cADPR介导的Ca 2+和线粒体DNA（mtDNA）释放到胞质溶胶中，这与NLRP 3炎性小体激活和VSMCs增殖和胶原I合成有关。最后，我们发现CD 38抑制剂、烟酰胺和替米沙坦显著改善了糖尿病小鼠的内皮非依赖性收缩和血管重构，这也与抑制主动脉中膜中的NLRP 3炎性小体有关。重要性：提示CD 38/cADPR介导的Ca ~（2+）信号通路导致线粒体损伤，线粒体DNA释放到胞浆中，与NLRP 3炎性小体激活和VSMCs重塑有关。
Aims: NLR family pyrin domain containing 3 (NLRP3) inflammasome activation contributes to the development of diabetic cardiovascular complications. CD38 regulates vascular inflammation through cyclic ADP-ribose (cADPR)-mediated Ca2+ signaling in vascular smooth muscle cells (VSMCs). Ca2+ mobilization may modulate inflammasome activation by impacting mitochondrial function. However, it remains unclear whether CD38 regulates NLRP3 inflammasome activation in VSMCs through cADPR-dependent Ca2+ release under diabetic condition.Main methods and key findings: In VSMCs, we observed that high glucose (HG, 30 mM) enhanced CD38 protein expression and ADP ribosyl cyclase activity. Moreover, along with less abundance of NLRP3, apoptosisassociated speck-like protein containing CARD (ASC) and their colocalization, the expression of active caspase1(p20) and IL-1 beta were significantly inhibited by CD38 gene deficiency with siRNA transfection in VSMCs. Further, CD38 regulated the release of intracellular cADPR-mediated Ca2+ and mitochondrial DNA (mtDNA) to the cytosol, which was associated with NLRP3 inflammasome activation and VSMCs proliferation and collagen I synthesis. Finally, we found that CD38 inhibitors, nicotinamide and telmisartan significantly improved the endothelium-independent contraction and vascular remodeling, which was also associated with the inhibition of NLRP3 inflammasome in the aorta media in the diabetic mice. Significance: Our data suggested that CD38/cADPR-mediated Ca2+ signaling contributed to the mitochondrial damage, consequently released mtDNA to the cytosol, which was related with NLRP3 inflammasome activation and VSMCs remodeling in diabetic mice.