title: Ascending aortic adventitial remodeling and fibrosis are ameliorated with Apelin-13 in rats after TAC via suppression of the miRNA-122 and LGR4-β-catenin signaling.
abstract: Apelin has been proved to be a critical mediator of vascular function and homeostasis. Here, we investigated roles of Apelin in aortic remodeling and fibrosis in rats with transverse aortic constriction (TAC). Male Sprague-Dawley rats were subjected to TAC and then randomized to daily deliver Apelin-13 (50μg/kg) or angiotensin type 1 receptor (AT1) blocker Irbesartan (50mg/kg) for 4 weeks. Pressure overload resulted in myocardial hypertrophy, systolic dysfunction, aortic remodeling and adventitial fibrosis with reduced levels of Apelin in ascending aortas of rat after TAC compared with sham-operated group. These changes were associated with marked increases in levels of miRNA-122, TGFβ1, CTGF, NFAT5, LGR4, and β-catenin. More importantly, Apelin and Irbesartan treatment strikingly prevented TAC-mediated aortic remodeling and adventitial fibrosis in pressure overloaded rats by blocking AT1 receptor and miRNA-122 levels and repressing activation of the CTGF-NFAT5 and LGR4-β-catenin signaling. In cultured primary rat adventitial fibroblasts, exposure to angiotensin II (100nmolL-1) led to significant increases in cellular migration and levels of TGFβ1, CTGF, NFAT5, LGR4 and β-catenin, which were effectively reversed by pre-treatment with Apelin (100nmolL-1) and miRNA-122 inhibitor (50nmolL-1). In conclusion, Apelin counterregulated against TAC-mediated ascending aortic remodeling and angiotensin II-induced promotion of cellular migration by blocking AT1 receptor and miRNA-122 levels and preventing activation of the TGFβ1-CTGF-NFAT5 and LGR4-β-catenin signaling, ultimately contributing to attenuation of aortic adventitial fibrosis. Our data point to Apelin as an important regulator of aortic remodeling and adventitial fibrosis and a promising target for vasoprotective therapies.
authors: State Key Laboratory of Medical Genomics, Pôle Sino-Français de Recherches en Science du Vivant et Génomique, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Shanghai 200025, China; Institute of Health Sciences, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai 200025, China.
authors: Ran
authors: R
authors: Xu
authors: State Key Laboratory of Medical Genomics, Pôle Sino-Français de Recherches en Science du Vivant et Génomique, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Shanghai 200025, China; Institute of Health Sciences, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai 200025, China.
authors: Zhen-Zhou
authors: ZZ
authors: Zhang
authors: State Key Laboratory of Medical Genomics, Pôle Sino-Français de Recherches en Science du Vivant et Génomique, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Shanghai 200025, China; Institute of Health Sciences, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai 200025, China.
authors: Lai-Jiang
authors: LJ
authors: Chen
authors: Department of Cardiology, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou 510080, China.
authors: Hui-Min
authors: HM
authors: Yu
authors: State Key Laboratory of Medical Genomics, Pôle Sino-Français de Recherches en Science du Vivant et Génomique, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Shanghai 200025, China.
authors: Shu-Jie
authors: SJ
authors: Guo
authors: State Key Laboratory of Medical Genomics, Pôle Sino-Français de Recherches en Science du Vivant et Génomique, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Shanghai 200025, China.
authors: Ying-Le
authors: YL
authors: Xu
authors: Department of Medicine, University of Alberta, Mazankowski Alberta Heart Institute, Edmonton T6G 2S2, Canada.
authors: Gavin Y
authors: GY
authors: Oudit
authors: State Key Laboratory of Medical Genomics, Pôle Sino-Français de Recherches en Science du Vivant et Génomique, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Shanghai 200025, China.
authors: Yan
authors: Y
authors: Zhang
authors: State Key Laboratory of Medical Genomics, Pôle Sino-Français de Recherches en Science du Vivant et Génomique, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Shanghai 200025, China.
authors: Qing
authors: Q
authors: Chang
authors: State Key Laboratory of Medical Genomics, Pôle Sino-Français de Recherches en Science du Vivant et Génomique, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Shanghai 200025, China.
authors: Bei
authors: B
authors: Song
authors: State Key Laboratory of Medical Genomics, Pôle Sino-Français de Recherches en Science du Vivant et Génomique, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Shanghai 200025, China.
authors: Dong-Rui
authors: DR
authors: Chen
authors: State Key Laboratory of Medical Genomics, Pôle Sino-Français de Recherches en Science du Vivant et Génomique, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Shanghai 200025, China; Institute of Health Sciences, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai 200025, China.
authors: Ding-Liang
authors: DL
authors: Zhu
authors: State Key Laboratory of Medical Genomics, Pôle Sino-Français de Recherches en Science du Vivant et Génomique, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Shanghai 200025, China; Institute of Health Sciences, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai 200025, China. Electronic address: jiuchangzhong@aliyun.com.
authors: Jiu-Chang
authors: JC
authors: Zhong
mesh_terms: D063194:Adventitia / Q000473:pathology*; D000818:Animals; D001011:Aorta / Q000473:pathology*; D017545:Aortic Aneurysm, Thoracic / Q000378:metabolism / Q000473:pathology*; D006332:Cardiomegaly / Q000378:metabolism; D002478:Cells, Cultured; D005355:Fibrosis; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology / Q000502:physiology*; D008297:Male; D035683:MicroRNAs / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D066253:Vascular Remodeling; D020257:Ventricular Remodeling; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism
chemical_list: C495268:Ctnnb1 protein, rat; D036341:Intercellular Signaling Peptides and Proteins; C116883:LGR4 receptor, rat; C580643:MIRN122 microRNA, rat; D035683:MicroRNAs; C492199:Nfat5 protein, rat; D043562:Receptors, G-Protein-Coupled; D014157:Transcription Factors; C495199:apelin-13 peptide; D051176:beta Catenin
keywords: Adventitial fibrosis; Angiotensin II; Aortic remodeling; Apelin; LGR4; Pressure overload