In:
Aging Cell, Wiley, Vol. 16, No. 6 ( 2017-12), p. 1334-1341
Abstract:
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 (ox LDL ) promoted apoptosis and osteoblastic differentiation of VIC via CHOP activation. Using conditioned media ( CM ) from ox LDL ‐treated VIC , we further identified that ox LDL triggered osteoblastic differentiation of VIC via paracrine pathway, while depletion of apoptotic bodies ( AB s) in CM suppressed the effect. CM from ox LDL ‐exposed CHOP ‐silenced cells prevented osteoblastic differentiation of VIC , while depletion of AB s 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 ox LDL ‐induced VIC osteoblastic differentiation via preventing VIC ‐derived AB s releasing.
Type of Medium:
Online Resource
ISSN:
1474-9718
,
1474-9726
DOI:
10.1111/acel.2017.16.issue-6
Language:
English
Publisher:
Wiley
Publication Date:
2017
detail.hit.zdb_id:
2099130-7
SSG:
12
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