Deficiency of CCAAT/enhancer-binding protein homologous protein (CHOP) prevents diet-induced aortic valve calcification in vivo.
Deficiency of CCAAT/enhancer-binding protein homologous protein (CHOP) prevents diet-induced aortic valve calcification in vivo.
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CCAAT/增强子结合蛋白同源蛋白（CHOP）的缺乏可防止体内饮食诱导的主动脉瓣钙化
DOI：
10.1111/acel.12674
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发表时间：
2017-12
期刊：
影响因子：
7.8
通讯作者：
Xiang M
中科院分区：
文献类型：
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作者：
Cai Z;Liu B;Wei J;Fu Z;Wang Y;Wang Y;Shen J;Jia L;Su S;Wang X;Lin X;Chen H;Li F;Wang J;Xiang M
主动脉瓣（AoV）钙化在老年人中很常见。其随后的主动脉狭窄与发病率增加有关，但仍然没有有效的药物干预。我们之前的数据显示内质网（ER）应激参与了AoV钙化。在这里，我们研究了内质网应激下游效应物CCAAT/增强子结合蛋白同源蛋白（CHOP）的缺乏是否可能阻止AoV钙化的发展。用Apoe−/−小鼠（n = 10）或Apoe和CHOP双重缺乏小鼠（Apoe−/−CHOP−/−,n = 10）饲喂西方饲料24周，评估AoV钙化情况。组织学和超声心动图分析显示，CHOP基因消融可减弱Apoe−/−小鼠小叶AoV钙化、促钙化信号激活和细胞凋亡。在体外培养的人主动脉瓣间质细胞（VIC）中，我们发现氧化低密度脂蛋白（oxLDL）通过CHOP激活促进VIC细胞凋亡和成骨细胞分化。使用条件培养基（CM），我们进一步发现oxLDL通过旁分泌途径触发VIC成骨细胞分化，而CM中凋亡小体（ABs）的消耗抑制了这一作用。来自暴露于oxLDL的CHOP沉默细胞的CM阻止了VIC的成骨细胞分化，而ABs的消耗并没有进一步增强这种保护作用。总的来说，我们的研究表明CHOP缺乏可以保护Apoe - / -小鼠免受西方饮食诱导的AoV钙化。CHOP缺乏通过阻止VIC来源的抗体释放来阻止oxLDL诱导的VIC成骨细胞分化。
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.
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影响因子：
39.3
作者：
Iung, B;Baron, G;Vahanian, A
通讯作者：
Vahanian, A
影响因子：
5
作者：
Gabunia K;Herman AB;Ray M;Kelemen SE;England RN;DeLa Cadena R;Foster WJ;Elliott KJ;Eguchi S;Autieri MV
通讯作者：
Autieri MV
DOI：
10.1161/atvbaha.112.300794
发表时间：
2013-03
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Chu Y;Lund DD;Weiss RM;Brooks RM;Doshi H;Hajj GP;Sigmund CD;Heistad DD
通讯作者：
Heistad DD
影响因子：
4.6
作者：
Jian, B;Narula, N;Levy, RJ
通讯作者：
Levy, RJ
影响因子：
9
作者：
通讯作者：
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