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

Zhejun Cai,Jian'An Wang,Baoqing Liu,Shengan Su,Fei Li,Zurong Fu,Liangliang Jia,Meixiang Xiang,Xiaoping Lin,Yaping Wang,Jia Wei,Yidong Wang,Xiaoya Wang,Han Chen,Jian Shen

doi:10.1111/acel.12674

Abstract

SummaryAortic 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.

Highlights

Calcified aortic valve disease (CAVD) is the most common valvular disease in the Western World (Nkomo et al, 2006)
endoplasmic reticulum (ER) stress signaling is composed of three signaling axes that are initiated by inositolrequiring protein-1 (IRE1), double-stranded RNA-dependent protein kinase-like ER kinase (PERK), and activating transcription factor 6 (ATF6) (Hetz, 2012)
Our previous study found CCAAT/enhancerbinding protein homology protein (CHOP) was activated in aortic valve (AoV) calcification (Cai et al, 2013), here we investigated whether CHOP plays a role in AoV

Summary

Introduction

Calcified aortic valve disease (CAVD) is the most common valvular disease in the Western World (Nkomo et al, 2006). CAVD may develop into aortic valve (AoV) stenosis. In the past decades, accumulating evidences suggest that AoV calcification is not a passive degenerative process, but an active disease progress including lipoprotein deposition, chronic inflammation, and osteoblastic differentiation of valvular interstitial cells (VIC) (Mathieu et al, 2014; Lerman et al, 2015). Disruption of ER homeostasis causes accumulation of unfolded and misfolded proteins in the ER lumen, leading to activation of ER stress signaling. Our previous study indicates that ER stress participates in the development of AoV calcification (Cai et al, 2013)

Objectives

Results

Discussion

Conclusion