title: Deregulation of XBP1 expression contributes to myocardial vascular endothelial growth factor-A expression and angiogenesis during cardiac hypertrophy in vivo.
abstract: Endoplasmic reticulum (ER) stress has been reported to be involved in many cardiovascular diseases such as atherosclerosis, diabetes, myocardial ischemia, and hypertension that ultimately result in heart failure. XBP1 is a key ER stress signal transducer and an important pro-survival factor of the unfolded protein response (UPR) in mammalian cells. The aim of this study was to establish a role for XBP1 in the deregulation of pro-angiogenic factor VEGF expression and potential regulatory mechanisms in hypertrophic and failing heart. Western blots showed that myocardial XBP1s protein was significantly increased in both isoproterenol (ISO)-induced and pressure-overload-induced hypertrophic and failing heart compared to normal control. Furthermore, XBP1 silencing exacerbates ISO-induced cardiac dysfunction along with a reduction of myocardial capillary density and cardiac expression of pro-angiogenic factor VEGF-A in vivo. Consistently, experiments in cultured cardiomyocytes H9c2 (2-1) cells showed that UPR-induced VEGF-A upregulation was determined by XBP1 expression level. Importantly, VEGF-A expression was increased in failing human heart tissue and blood samples and was correlated with the levels of XBP1. These results suggest that XBP1 regulates VEGF-mediated cardiac angiogenesis, which contributes to the progression of adaptive hypertrophy, and might provide novel targets for prevention and treatment of heart failure.
authors.affiliation: Division of Cardiology, Department Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.
authors.forename: Quanlu
authors.initials: Q
authors.lastname: Duan
authors.affiliation: Division of Cardiology, Department Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.
authors.forename: Li
authors.initials: L
authors.lastname: Ni
authors.affiliation: Division of Cardiology, Department Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.
authors.forename: Peihua
authors.initials: P
authors.lastname: Wang
authors.affiliation: Division of Cardiology, Department Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
authors.affiliation: Division of Cardiology, Department Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.
authors.forename: Lei
authors.initials: L
authors.lastname: Yang
authors.affiliation: Division of Cardiology, Department Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.
authors.forename: Ben
authors.initials: B
authors.lastname: Ma
authors.affiliation: Division of Cardiology, Department Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.
authors.forename: Wei
authors.initials: W
authors.lastname: Gong
authors.affiliation: Division of Cardiology, Department Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.
authors.forename: Zhejun
authors.initials: Z
authors.lastname: Cai
authors.affiliation: Center for Molecular and Translational Medicine, Georgia State University, Atlanta, 30303, GA, USA.
authors.forename: Ming-Hui
authors.initials: MH
authors.lastname: Zou
authors.affiliation: Division of Cardiology, Department Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.
authors.forename: Dao Wen
authors.initials: DW
authors.lastname: Wang
mesh_terms: D000368:Aged; D000818:Animals; D002196:Capillaries / Q000187:drug effects / Q000473:pathology; D006332:Cardiomegaly / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D002460:Cell Line; D000229:Dependovirus / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000235:genetics; D005260:Female; D020868:Gene Silencing; D006333:Heart Failure / Q000150:complications / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D007545:Isoproterenol; D008297:Male; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D008954:Models, Biological; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000235:genetics*; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D056811:Unfolded Protein Response / Q000235:genetics; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D000071717:X-Box Binding Protein 1 / Q000235:genetics* / Q000378:metabolism
chemical_list: D034741:RNA, Small Interfering; D042461:Vascular Endothelial Growth Factor A; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C000605544:Xbp1 protein, mouse; C000605545:Xbp1 protein, rat; D007545:Isoproterenol
keywords: XBP1; angiogenesis; cardiac hypertrophy; unfolded protein response; vascular endothelial growth factor-A