Department of Clinical Pharmacy, School of Preclinical Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
Department of Cardiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China.
Life Sci. 2020 Aug 15;255:117758. doi: 10.1016/j.lfs.2020.117758. Epub 2020 May 11.
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 Ca signaling in vascular smooth muscle cells (VSMCs). Ca mobilization may modulate inflammasome activation by impacting mitochondrial function. However, it remains unclear whether CD38 regulates NLRP3 inflammasome activation in VSMCs through cADPR-dependent Ca 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, apoptosis-associated speck-like protein containing CARD (ASC) and their colocalization, the expression of active caspase-1(p20) and IL-1β were significantly inhibited by CD38 gene deficiency with siRNA transfection in VSMCs. Further, CD38 regulated the release of intracellular cADPR-mediated Ca 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.
Our data suggested that CD38/cADPR-mediated Ca 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.
NLR 家族包含 pyrin 结构域蛋白 3（NLRP3）炎性小体的激活导致糖尿病心血管并发症的发生。CD38 通过血管平滑肌细胞（VSMCs）中循环 ADP-核糖（cADPR）介导的 Ca 信号调节血管炎症。Ca 动员可能通过影响线粒体功能来调节炎性小体的激活。然而，在糖尿病条件下，CD38 是否通过 cADPR 依赖性 Ca 释放来调节 VSMCs 中的 NLRP3 炎性小体激活仍不清楚。
在 VSMCs 中，我们观察到高葡萄糖（HG，30 mM）增强了 CD38 蛋白表达和 ADP 核糖基环化酶活性。此外，随着 NLRP3、凋亡相关斑点样蛋白（ASC）及其共定位的丰度降低，用 siRNA 转染 VSMCs 中的 CD38 基因缺失明显抑制了活性半胱天冬酶-1（p20）和 IL-1β的表达。此外，CD38 调节细胞内 cADPR 介导的 Ca 和线粒体 DNA（mtDNA）释放到细胞质，这与 NLRP3 炎性小体激活以及 VSMCs 增殖和胶原 I 合成有关。最后，我们发现 CD38 抑制剂烟酰胺和替米沙坦显著改善了糖尿病小鼠主动脉中层的内皮非依赖性收缩和血管重塑，这也与 NLRP3 炎性小体的抑制有关。
我们的数据表明，CD38/cADPR 介导的 Ca 信号导致线粒体损伤，随后将 mtDNA 释放到细胞质中，这与糖尿病小鼠中 NLRP3 炎性小体激活和 VSMCs 重塑有关。
