title: Luteolin-7-diglucuronide attenuates isoproterenol-induced myocardial injury and fibrosis in mice.
abstract: Myocardial injury and ensuing fibrotic alterations impair normal heart architecture and cause cardiac dysfunction. Oxidative stress has been recognized as a key player in the pathogenesis of cardiac injury and progression of cardiac dysfunction, and promoting fibrosis. In the current study we investigated whether luteolin-7-diglucuronide (L7DG), a naturally occurring antioxidant found in edible plants, could attenuate isoproterenol (ISO)-induced myocardial injury and fibrosis in mice and the underlying mechanisms. Myocardial injury and fibrosis were induced in mice via injection of ISO (5 mg·kg-1·d-1, ip) for 5 or 10 d. Two treatment regimens (pretreatment and posttreatment) were employed to administer L7DG (5-40 mg·kg-1·d-1, ip) into the mice. After the mice were euthanized, morphological examinations of heart sections revealed that both L7DG pretreatment and posttreatment regimens significantly attenuated ISO-induced myocardial injury and fibrosis. But the pretreatment regimen caused better protection against ISO-induced myocardial fibrosis than the posttreatment regimen. Furthermore, L7DG pretreatment blocked ISO-stimulated expression of the genes (Cyba, Cybb, Ncf1, Ncf4 and Rac2) encoding the enzymatic subunits of NADPH oxidase, which was the primary source of oxidant production in mammalian cells. Moreover, L7DG pretreatment significantly suppressed ISO-stimulated expression of collagen genes Col1a1, Col1a2, Col3a1, and Col12a1 and non-collagen extracellular matrix genes fibrillin-1, elastin, collagen triple helix repeat containing 1 and connective tissue growth factor. In addition, L7DG pretreatment almost reversed ISO-altered expression of microRNAs that were crosstalking with TGFβ-mediated fibrosis, including miR-29c-3p, miR-29c-5p, miR-30c-3p, miR-30c-5p and miR-21. The current study demonstrated for the first time that L7DG is pharmacologically effective in protecting the heart against developing ISO-induced injury and fibrosis, justifying further evaluation of L7DG as a cardioprotective agent to treat related cardiovascular diseases.
authors.affiliation: Clinical Research Institute of Integrative Medicine, and Yueyang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China.
authors.forename: Bing-Bing
authors.initials: BB
authors.lastname: Ning
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Clinical Research Institute of Integrative Medicine, and Yueyang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China.
authors.forename: Dan-Dan
authors.initials: DD
authors.lastname: Wu
authors.affiliation: Clinical Research Institute of Integrative Medicine, and Yueyang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China.
authors.forename: Jin-Gang
authors.initials: JG
authors.lastname: Cui
authors.affiliation: Clinical Research Institute of Integrative Medicine, and Yueyang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China.
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.affiliation: Clinical Research Institute of Integrative Medicine, and Yueyang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China.
authors.forename: Pei-Wei
authors.initials: PW
authors.lastname: Wang
authors.affiliation: Clinical Research Institute of Integrative Medicine, and Yueyang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China.
authors.forename: Wen-Jian
authors.initials: WJ
authors.lastname: Wang
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Wei-Liang
authors.initials: WL
authors.lastname: Zhu
authors.affiliation: Clinical Research Institute of Integrative Medicine, and Yueyang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Clinical Research Institute of Integrative Medicine, and Yueyang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China.
authors.forename: Teng
authors.initials: T
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology* / Q000627:therapeutic use; D009202:Cardiomyopathies / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D002316:Cardiotonic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D005355:Fibrosis / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D005965:Glucuronates / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use; D007545:Isoproterenol; D019686:Lamiaceae / Q000737:chemistry; D047311:Luteolin / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000378:metabolism; D009206:Myocardium / Q000473:pathology*; D009336:Necrosis / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology
chemical_list: D000975:Antioxidants; D002316:Cardiotonic Agents; D016326:Extracellular Matrix Proteins; D005965:Glucuronates; D035683:MicroRNAs; C096572:luteolin 7-diglucuronide; D047311:Luteolin; D007545:Isoproterenol