Deficiency of CCAAT/enhancer-binding protein homologous protein (CHOP) prevents diet-induced aortic valve calcification in vivo

被引：9

作者：

Cai, Zhejun ^{[1
]}

Liu, Baoqing ^{[2
]}

Wei, Jia

Fu, Zurong ^{[1
]}

Wang, Yidong ^{[1
]}

Wang, Yaping ^{[1
]}

Shen, Jian ^{[1
]}

Jia, Liangliang ^{[1
]}

Su, Shengan ^{[1
]}

Wang, Xiaoya ^{[1
]}

Lin, Xiaoping ^{[1
]}

Chen, Han ^{[1
]}

Li, Fei ^{[2
]}

Wang, Jian'an ^{[1
]}

Xiang, Meixiang ^{[1
]}

机构：

[1] Zhejiang Univ, Sch Med, Affiliated Hosp 2, Dept Cardiol, Hangzhou 310009, Zhejiang, Peoples R China

[2] Huazhong Univ Sci & Technol, Union Hosp, Dept Cardiovasc Surg, Tongji Med Coll, Wuhan 430030, Hubei, Peoples R China

来源：

AGING CELL | 2017年 / 16卷 / 06期

基金：

中国国家自然科学基金;

关键词：

aortic valve calcification; apoptotic bodies; apoptosis; CHOP; endoplasmic reticulum stress; ENDOPLASMIC-RETICULUM STRESS; SMOOTH-MUSCLE-CELLS; INTERSTITIAL-CELLS; ER STRESS; OSTEOGENIC RESPONSES; KINASE ALPHA-1; DISEASE; PROGRESSION; APOPTOSIS; PROLIFERATION;

D O I：

10.1111/acel.12674

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Aortic valve (AoV) calcification is common in aged populations. Its subsequent aortic stenosis has been linked with increased morbidity, but still has no effective pharmacological intervention. Our previous data show endoplasmic reticulum (ER) stress is involved in AoV calcification. Here, we investigated whether deficiency of ER stress downstream effector CCAAT/enhancer-binding protein homology protein (CHOP) may prevent development of AoV calcification. AoV calcification was evaluated in Apoe(-/-) mice (n=10) or in mice with dual deficiencies of ApoE and CHOP (Apoe(-/-)CHOP(-/-), n=10) fed with Western diet for 24 weeks. Histological and echocardiographic analysis showed that genetic ablation of CHOP attenuated AoV calcification, pro-calcification signaling activation, and apoptosis in the leaflets of Apoe(-/-) mice. In cultured human aortic valvular interstitial cells (VIC), we found oxidized low-density lipoprotein (oxLDL) promoted apoptosis and osteoblastic differentiation of VIC via CHOP activation. Using conditioned media (CM) from oxLDL-treated VIC, we further identified that oxLDL triggered osteoblastic differentiation of VIC via paracrine pathway, while depletion of apoptotic bodies (ABs) in CM suppressed the effect. CM from oxLDL-exposed CHOP-silenced cells prevented osteoblastic differentiation of VIC, while depletion of ABs did not further enhance this protective effect. Overall, our study indicates that CHOP deficiency protects against Western diet-induced AoV calcification in Apoe(-/-) mice. CHOP deficiency prevents oxLDL-induced VIC osteoblastic differentiation via preventing VIC-derived ABs releasing.

引用

页码：1334 / 1341

页数：8

共 35 条

[1] Arterial and Aortic Valve Calcification Abolished by Elastolytic Cathepsin S Deficiency in Chronic Renal Disease [J].