title: Puerarin-7-O-glucuronide, a water-soluble puerarin metabolite, prevents angiotensin II-induced cardiomyocyte hypertrophy by reducing oxidative stress.
abstract: This study aimed to investigate the anti-oxidant and anti-hypertrophic effects of puerarin-7-O-glucuronide, a water-soluble puerarin metabolite. The anti-oxidant effects of puerarin-7-O-glucuronide were assessed by measurement of intracellular superoxide levels, total superoxide dismutase (SOD) activity, total anti-oxidant capacity, and glutathione (GSH)/glutathione disulfide (GSSG) ratio in cultured neonatal rat cardiomyocytes (NRCMs) stimulated with the xanthine oxidase (XO)/xanthine (X) system or angiotensin II. The activity of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and expression of NADPH oxidase subunits p22phoxand p47phoxwere determined. The anti-hypertrophic effects of puerarin-7-O-glucuronide in angiotensin II-challenged NRCMs were characterized by changes in cell morphology and expression of hypertrophic genes. In the pharmacokinetic study, the plasma concentration of puerarin-7-O-glucuronide was determined by rapid resolution-liquid chromatography-tandem mass spectrometry (RR-LC-MS/MS). Puerarin-7-O-glucuronide prevented XO/X-induced increase in intracellular superoxide production and decreases in total SOD activity, GSH/GSSG ratio, and total anti-oxidant capacity. Puerarin-7-O-glucuronide also reversed angiotensin II-induced increases in intracellular superoxide production and NADPH oxidase activity and decreases in total SOD activity. These anti-oxidant effects of puerarin-7-O-glucuronide were accompanied by downregulation of p22phoxand p47phox. Furthermore, puerarin-7-O-glucuronide prevented angiotensin II-induced increases in cell surface area and perimeter, as well as changes in Nppa, Myh7, and Myh6. In the pharmacokinetic study, puerarin-7-O-glucuronide was cleared with a half-life of 0.94 h after intravenous administration. Puerarin could be detected in rat plasma, albeit in low concentration, as early as 5 min after intravenous administration of puerarin-7-O-glucuronide. These anti-oxidant and anti-hypertrophic properties of puerarin-7-O-glucuronide were similar to those of its parent compound puerarin. These results support the development of puerarin-7-O-glucuronide as a novel pharmaceutical agent for therapeutic application.
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, 511436, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Hou
authors.affiliation: Changsha Central Hospital, 161 Shaoshannan Road, Changsha, 410018, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Cai
authors.affiliation: Department of Cardiology, Guangdong Provincial Center of Biomedical Engineering for Cardiovascular Disease, Zhujiang Hospital of Southern Medical University, 253 Gongye Avenue, Guangzhou, 510280, China.
authors.forename: Cai-Wen
authors.initials: CW
authors.lastname: Ou
authors.affiliation: Department of Cardiology, Guangzhou Institute of Cardiovascular Disease, The Second Affiliated Hospital of Guangzhou Medical University, 250 Changgangdong Road, Guangzhou, 510260, China.
authors.forename: Zhen-Hui
authors.initials: ZH
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, 511436, China.
authors.forename: Xia-Wen
authors.initials: XW
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, 511436, China.
authors.forename: Mu
authors.initials: M
authors.lastname: Yuan
authors.affiliation: Department of Cardiology, Guangzhou Institute of Cardiovascular Disease, The Second Affiliated Hospital of Guangzhou Medical University, 250 Changgangdong Road, Guangzhou, 510260, China.
authors.forename: Gan-Jian
authors.initials: GJ
authors.lastname: Zhao
authors.affiliation: Department of Cardiology, Guangzhou Institute of Cardiovascular Disease, The Second Affiliated Hospital of Guangzhou Medical University, 250 Changgangdong Road, Guangzhou, 510260, China.
authors.forename: Shi-Ming
authors.initials: SM
authors.lastname: Liu
authors.affiliation: Department of Cardiology, Guangzhou Institute of Cardiovascular Disease, The Second Affiliated Hospital of Guangzhou Medical University, 250 Changgangdong Road, Guangzhou, 510260, China.
authors.forename: Long-Gen
authors.initials: LG
authors.lastname: Xiong
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, 511436, China.
authors.forename: Jian-Dong
authors.initials: JD
authors.lastname: Luo
authors.affiliation: Department of Cardiology, Guangzhou Institute of Cardiovascular Disease, The Second Affiliated Hospital of Guangzhou Medical University, 250 Changgangdong Road, Guangzhou, 510260, China. rocenphone@gzhmu.edu.cn.
authors.forename: Cheng-Feng
authors.initials: CF
authors.lastname: Luo
authors.affiliation: Department of Cardiology, Guangdong Provincial Center of Biomedical Engineering for Cardiovascular Disease, Zhujiang Hospital of Southern Medical University, 253 Gongye Avenue, Guangzhou, 510280, China. gzminsheng@vip.163.com.
authors.forename: Min-Sheng
authors.initials: MS
authors.lastname: Chen
mesh_terms: D000804:Angiotensin II / Q000633:toxicity*; D000818:Animals; D000831:Animals, Newborn; D000975:Antioxidants / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D006332:Cardiomegaly / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002478:Cells, Cultured; D005260:Female; D020719:Glucuronides / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism; D007275:Injections, Intravenous; D007529:Isoflavones / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D017207:Rats, Sprague-Dawley; D012995:Solubility; D012997:Solvents / Q000737:chemistry*; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D014867:Water / Q000737:chemistry*; D019820:Xanthine / Q000494:pharmacology; D014969:Xanthine Oxidase / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D020719:Glucuronides; D007529:Isoflavones; D012997:Solvents; C580761:puerarin-7-O-glucuronide; D014867:Water; D013481:Superoxides; D000804:Angiotensin II; D019820:Xanthine; D013482:Superoxide Dismutase; D014969:Xanthine Oxidase; D019255:NADPH Oxidases; D005978:Glutathione; D019803:Glutathione Disulfide
keywords: Cardiomyocyte hypertrophy; Metabolism; Oxidative stress; Pharmacokinetics; Puerarin; Puerarin-7-O-glucuronide