Regulation of NLRP3 inflammasome by CD38 through cADPR-mediated Ca release in vascular smooth muscle cells in diabetic mice.

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 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.

SIGNIFICANCE

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.