Deacetylation of cGAS by HDAC1 regulates vascular calcification by promoting autophagy.

AIMS: Vascular calcification is a major risk factor for cardiovascular mortality accompanied by DNA damage. Cyclic GMP-AMP synthase (cGAS) is a DNA sensor that is activated by genomic DNA damage. Here, we investigated the molecular mechanisms linking cGAS to vascular calcification. MAIN METHODS: Diabetic arteriosclerotic model and vascular calcification of primary vascular smooth muscle cells (VSMCs) were induced. Calcification was visualized with Alizarin red staining. Calcium deposition and alkaline phosphatase activity were analyzed by respectively kits. Deacetylation of cGAS was investigated using co-immunoprecipitation assay. KEY FINDINGS: Protein, but not mRNA, expression of cGAS is down-regulated in VSMCs and animal models of calcification. Overexpression of cGAS attenuated high-Pi induced calcification, calcium content and ALP activity. In addition, cGAS regulated VSMCs phenotype as overexpression of cGAS increased expression of contractile markers α-SMA and SM22α and decreased the expression of osteogenic markers RUNX2 and BMP2. The LC3II/LC3I ratio and Atg5 level were upregulated by cGAS overexpression. Under calcification-inducing conditions, HDAC1 deacetylates cGAS and inactivates it. HDAC1 knockdown by short hairpin HDAC1 reversed the cGAS-induced reduction in vascular calcification, as well as in autophagy. SIGNIFICANCE: HDAC1-induced cGAS deacetylation enhances vascular calcification and may therefore be a potential therapeutic target.