title: The cardioprotective effect of melatonin and exendin-4 treatment in a rat model of cardiorenal syndrome.
abstract: We investigated the cardioprotective effect of melatonin (Mel) and exendin-4 (Ex4) treatment in a rat model of cardiorenal syndrome (CRS). Adult male SD rats (n=48) were randomly and equally divided into sham control (SC), dilated cardiomyopathy (DCM) (doxorubicin 7 mg/kg i.p. every five days/4 doses), CRS (defined as DCM+CKD) only, CRS-Mel (20 mg/kg/d), CRS-Ex4 (10 μg/kg/d), and CRS-Mel-Ex4 groups. In vitro results showed protein expressions of oxidative stress (NOX-1/NOX-2/oxidized protein), DNA/mitochondrial damage (γ-H2AX/cytosolic cytochrome c), apoptosis (cleaved caspase-3/PARP), and senescence (β-galactosidase cells) biomarkers were upregulated, whereas mitochondrial ATP level was decreased in doxorubicin/p-cresol-treated H9c2 cells that were revised by Mel and Ex4 treatments (all P<.001). By day 60, LVEF was highest in the SC and lowest in the CRS, significantly lower in the DCM than in other treatment groups, lower in the CRS-Mel and CRS-Ex4 than in the CRS-Mel-Ex4, and lower in the CRS-Mel than in the CRS-Ex4, whereas LV chamber size and histopathology score showed a pattern opposite to that of LVEF among all groups (all P<.001). Plasma creatinine level was highest in the CRS and lowest in the SC and progressively decreased from the CRS-Mel, CRS-Ex4, CRS-Mel-Ex4 to DCM (P<.0001). Protein expressions of inflammation (TNF-α/NF-κB/MMP-2/MMP-9/IL-1β), apoptosis/DNA damage (Bax/c-caspase-3/c-PARP/γ-H2AX), fibrosis (Smad3/TGF-β), oxidative stress (NOX-1/NOX-2/NOX-4/oxidized protein), cardiac hypertrophy/pressure overload (BNP/β-MHC), and cardiac integrity (Cx43/α-MHC) biomarkers in LV myocardium showed an opposite pattern compared to that of LVEF among all groups (all P<.001). Fibrotic area, DNA damage (γ-H2AX+/53BP1+CD90+/XRCC1+CD90+), and inflammation (CD14+/CD68+) biomarkers in LV myocardium displayed a pattern opposite to that of LVEF among all groups (all P<.001). Combined melatonin and exendin-4 treatment suppressed CRS-induced deterioration of LVEF and LV remodeling.
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan. chuasr409@hotmail.com.
authors.forename: Sarah
authors.initials: S
authors.lastname: Chua
authors.affiliation: Division of thoracic and Cardiovascular Surgery, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Fan-Yen
authors.initials: FY
authors.lastname: Lee
authors.affiliation: Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Hsin-Ju
authors.initials: HJ
authors.lastname: Chiang
authors.affiliation: Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan.|Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Kuan-Hung
authors.initials: KH
authors.lastname: Chen
authors.affiliation: Division of thoracic and Cardiovascular Surgery, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Hung-I
authors.initials: HI
authors.lastname: Lu
authors.affiliation: Division of Urology, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Yen-Ta
authors.initials: YT
authors.lastname: Chen
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Chih-Chao
authors.initials: CC
authors.lastname: Yang
authors.affiliation: Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Kun-Chen
authors.initials: KC
authors.lastname: Lin
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Yi-Ling
authors.initials: YL
authors.lastname: Chen
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Gour-Shenq
authors.initials: GS
authors.lastname: Kao
authors.affiliation: Divisions of General Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Chih-Hung
authors.initials: CH
authors.lastname: Chen
authors.affiliation: Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan.
authors.forename: Hsueh-Wen
authors.initials: HW
authors.lastname: Chang
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan. han.gung@msa.hinet.net.|Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan. han.gung@msa.hinet.net.|Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan. han.gung@msa.hinet.net.|Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan. han.gung@msa.hinet.net.|Department of Nursing, Asia University, Taichung, Taiwan. han.gung@msa.hinet.net.
authors.forename: Hon-Kan
authors.initials: HK
authors.lastname: Yip
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D059347:Cardio-Renal Syndrome / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004249:DNA Damage; D004195:Disease Models, Animal; D000077270:Exenatide; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D008550:Melatonin / Q000494:pharmacology*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D010455:Peptides / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014688:Venoms / Q000494:pharmacology*
chemical_list: D002316:Cardiotonic Agents; D010455:Peptides; D014688:Venoms; D000077270:Exenatide; D008550:Melatonin
keywords: LV remodeling; cardiorenal disease; exendin-4; heart function; melatonin