HDAC2 counteracts vascular calcification by activating autophagy in chronic kidney disease

Abstract

Vascular calcification is a major risk factor for cardiovascular disease mortality, with a significant prevalence in chronic kidney disease (CKD). Pharmacological inhibition of histone acetyltransferase has been proven to protect against from vascular calcification. However, the role of Histone Deacetylase 2 (HDAC2) and molecular mechanisms in vascular calcification of CKD remains unknown. An in vivo model of CKD was established using mouse fed with a high adenine and phosphate diet, and an in vitro model was produced using human aortic vascular smooth muscle cells (VSMCs) stimulated with β‐glycerophosphate (β‐GP). HDAC2 expression was found to be reduced in medial artery of CKD mice and β‐GP‐induced VSMCs. Overexpression of HDAC2 attenuated OPN and OCN upregulation, α‐SMA and SM22α downregulation, and calcium deposition in aortas of CKD. The in vitro results also demonstrated that β‐GP‐induced osteogenic differentiation was inhibited by HDAC2. Furthermore, we found that HDAC2 overexpression caused an increase in LC3II/I, a decrease in p62, and an induction of autophagic flux. Inhibition of autophagy using its specific inhibitor 3‐MA blocked HDAC2's protective effect on osteogenic differentiation in β‐GP‐treated VSMCs. Taken together, these results suggest that HDAC2 may protect against vascular calcification by the activation of autophagy, laying out a novel insight for the molecular mechanism in vascular calcification of CKD.