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.
摘要：
血管钙化是心血管疾病死亡的主要危险因素,慢性肾脏病(CKD)患病率显著。组蛋白乙酰转移酶的药理学抑制已被证明可以防止血管钙化。然而,组蛋白去乙酰化酶2(HDAC2)在CKD血管钙化中的作用及其分子机制尚不清楚。用高腺嘌呤和磷酸盐饮食喂养小鼠建立CKD的体内模型，并使用β-甘油磷酸盐（β-GP）刺激的人主动脉血管平滑肌细胞（VSMC）产生体外模型。发现HDAC2在CKD小鼠和β-GP诱导的VSMC的内侧动脉中表达降低。HDAC2的过表达减弱了OPN和OCN的上调，α-SMA和SM22α下调，和钙在CKD主动脉中的沉积。体外结果还表明HDAC2抑制了β-GP诱导的成骨分化。此外，我们发现HDAC2过表达引起LC3II/I的增加，p62的减少和自噬通量的诱导。使用其特异性抑制剂3-MA抑制自噬可阻断HDAC2对β-GP处理的VSMCs成骨分化的保护作用。一起来看,这些结果表明，HDAC2可能通过激活自噬来防止血管钙化，为CKD血管钙化的分子机制提供了新的见解。
