title: Matrine attenuates cardiac fibrosis by affecting ATF6 signaling pathway in diabetic cardiomyopathy.
abstract: Cardiac function and compliance impairments are the features of cardiac fibrosis. Matrine shows therapeutic effects on cardiovascular diseases and organ fibrosis. In this study, we examined the therapeutic effects and mechanisms of matrine on cardiac fibrosis of DbCM. Matrine was administrated orally to rats with DbCM. Cardiac functions and compliance were evaluated. The collagen deposition was visualized by sirius red staining. Real-time PCR was used to determine the expression level of miRNA. Western blotting was performed to assess the protein expression. NFAT nuclear translocation was evaluated by fluorescent immunochemistry staining and Western blotting. Intracellular calcium level was assessed by fura-2/AM staining. A colorimetric method was used to determine calcineurin enzymatic activity. Impaired cardiac function and compliance were observed in rats with DbCM. Increased collagen deposition in cardiac tissue was found. Furthermore, ATF6 signaling was activated, leading to intracellular calcium accumulation and NFAT activation which further initiated ECM gene expressions. Matrine administration recovered cardiac function and improved compliance by exerting inhibitory effects against ATF6 signaling- induced fibrosis. The high- glucose incubation induced ATF6 signaling activation in cultured CFs to increase the synthesis of ECM. Matrine blocked the ATF6 signaling in CFs to inhibit ECM synthesis within non- cytotoxic concentrations. ATF6 signaling induced cardiac fibrosis was one of the mechanisms involved in DbCM, which was characterized by loss of cardiac compliance and functions. Matrine attenuated cardiac compliance and improved left ventricular functions by exerting therapeutic effects against cardiac fibrosis via affecting ATF6 signaling pathway.
authors.affiliation: Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an 710000, China; Institute of Molecular Genetics, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710000, China. Electronic address: liuzhongwei@xjtu.edu.cn.
authors.forename: Zhongwei
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an 710000, China. Electronic address: zhangyong971292@163.com.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an 710000, China. Electronic address: keplbr@sina.com.
authors.forename: Zhiguo
authors.initials: Z
authors.lastname: Tang
authors.affiliation: Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an 710000, China. Electronic address: hhjadk@sina.com.
authors.forename: Jing
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an 710000, China. Electronic address: mzjwoy@sina.com.
authors.forename: Meijuan
authors.initials: M
authors.lastname: Ma
authors.affiliation: Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an 710000, China. Electronic address: parker1985@163.com.
authors.forename: Shuo
authors.initials: S
authors.lastname: Pan
authors.affiliation: Department of Biostatistics & Bioinformatics, School of Public Health & Tropical Medicine, Tulane University, New Orleans 70112, USA. Electronic address: qcshare@gmail.com.
authors.forename: Chuan
authors.initials: C
authors.lastname: Qiu
authors.affiliation: Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an 710000, China. Electronic address: gongchang_guan@sina.com.
authors.forename: Gongchang
authors.initials: G
authors.lastname: Guan
authors.affiliation: Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an 710000, China. Electronic address: junkuiwang@yeah.net.
authors.forename: Junkui
authors.initials: J
authors.lastname: Wang
mesh_terms: D051702:Activating Transcription Factor 6 / Q000378:metabolism*; D000470:Alkaloids / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D037282:Calreticulin / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D058065:Diabetic Cardiomyopathies / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D003971:Diastole / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D005355:Fibrosis; D005947:Glucose / Q000494:pharmacology; D008297:Male; D009206:Myocardium / Q000473:pathology*; D050778:NFATC Transcription Factors / Q000378:metabolism; D011807:Quinolizines / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D013599:Systole / Q000187:drug effects; D000093842:Matrines
chemical_list: D051702:Activating Transcription Factor 6; D000470:Alkaloids; C497113:Atf6 protein, rat; D037282:Calreticulin; D050778:NFATC Transcription Factors; D011807:Quinolizines; D005947:Glucose; D000093842:Matrines
keywords: ATF6; Calcineurin; Calcium; Calreticulin; Cardiac fibroblasts; Diabetic cardiomyopathy; Fibrosis; Matrine