title: RAGE deficiency alleviates aortic valve calcification in ApoE-/-mice via the inhibition of endoplasmic reticulum stress.
abstract: Receptor for advanced glycation end products (RAGE) and endoplasmic reticulum (ER) stress have been shown to be involved in calcific aortic valve disease (CAVD). However, the association between RAGE and ER stress remains unknown in the pathogenesis of CAVD. The current study aims to test the hypothesis that RAGE deficiency alleviates aortic valve calcification via the inhibition of ER stress. Up-regulation of RAGE and ER stress markers in calcified human aortic valves were confirmed by immunoblotting. Aortic valve calcification was evaluated in atherosclerotic prone ApoE-/-mice or in mice with dual deficiencies of ApoE and RAGE (ApoE-/-RAGE-/-) fed with high cholesterol diet for 24weeks. Echocardiography and histological examination show that genetic deficiency of RAGE attenuates aortic valve calcification in ApoE-/-mice. Meanwhile, RAGE deficiency inhibited the osteogenic signaling and ER stress activation as well as suppressed macrophage infiltration in vivo. Cultured human aortic valve interstitial cells (AVICs) were treated with high molecular group box 1 protein (HMGB1) as in vitro model. We found that HMGB1 induced osteoblastic differentiation and calcification through RAGE/ER stress. Furthermore, Sox9 up-regulation and intranuclear translocation mediated the pro-osteogenic effect of HMGB1 on AVICs. RAGE or ER stress knockdown reduced the up-regulation of monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-α (TNF-α) in human AVICs exposed to HMGB1.These novel findings demonstrate that RAGE deficiency protects against aortic valve calcification in high cholesterol diet-fed ApoE-/-mice via inhibition of ER stress. HMGB1 induces AVIC osteoblastic differentiation and calcification through RAGE/ER stress/Sox9 pathway.
authors.affiliation: Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Cardiology, Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, China.
authors.forename: Zhejun
authors.initials: Z
authors.lastname: Cai
authors.affiliation: Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China.
authors.forename: Baoqing
authors.initials: B
authors.lastname: Liu
authors.affiliation: Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China.
authors.forename: Zongtao
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China.
authors.forename: Xianming
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China. Electronic address: dongnianguo@hotmail.com.
authors.forename: Nianguo
authors.initials: N
authors.lastname: Dong
authors.affiliation: Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China. Electronic address: lifei_union@sina.com.
authors.forename: Fei
authors.initials: F
authors.lastname: Li
mesh_terms: D000818:Animals; D001021:Aortic Valve / Q000378:metabolism / Q000473:pathology*; D001024:Aortic Valve Stenosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D001057:Apolipoproteins E / Q000235:genetics* / Q000378:metabolism; D002114:Calcinosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress; D017353:Gene Deletion; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D000067759:Receptor for Advanced Glycation End Products / Q000235:genetics* / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D000067759:Receptor for Advanced Glycation End Products; D002784:Cholesterol
keywords: Aortic valve calcification; ER stress; HMGB1; RAGE; Sox9