title: Adiponectin mediates cardioprotection in oxidative stress-induced cardiac myocyte remodeling.
abstract: Reactive oxygen species (ROS) induce matrix metalloproteinase (MMP) activity that mediates hypertrophy and cardiac remodeling. Adiponectin (APN), an adipokine, modulates cardiac hypertrophy, but it is unknown if APN inhibits ROS-induced cardiomyocyte remodeling. We tested the hypothesis that APN ameliorates ROS-induced cardiomyocyte remodeling and investigated the mechanisms involved. Cultured adult rat ventricular myocytes (ARVM) were pretreated with recombinant APN (30 μg/ml, 18 h) followed by exposure to physiologic concentrations of H(2)O(2) (1-200 μM). ARVM hypertrophy was measured by [(3)H]leucine incorporation and atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP) gene expression by RT-PCR. MMP activity was assessed by in-gel zymography. ROS was induced with angiotensin (ANG)-II (3.2 mg·kg(-1)·day(-1) for 14 days) in wild-type (WT) and APN-deficient (APN-KO) mice. Myocardial MMPs, tissue inhibitors of MMPs (TIMPs), p-AMPK, and p-ERK protein expression were determined. APN significantly decreased H(2)O(2)-induced cardiomyocyte hypertrophy by decreasing total protein, protein synthesis, ANF, and BNP expression. H(2)O(2)-induced MMP-9 and MMP-2 activities were also significantly diminished by APN. APN significantly increased p-AMPK in both nonstimulated and H(2)O(2)-treated ARVM. H(2)O(2)-induced p-ERK activity and NF-κB activity were both abrogated by APN pretreatment. ANG II significantly decreased myocardial p-AMPK and increased p-ERK expression in vivo in APN-KO vs. WT mice. ANG II infusion enhanced cardiac fibrosis and MMP-2-to-TIMP-2 and MMP-9-to-TIMP-1 ratios in APN-KO vs. WT mice. Thus APN inhibits ROS-induced cardiomyocyte remodeling by activating AMPK and inhibiting ERK signaling and NF-κB activity. Its effects on ROS and ultimately on MMP expression define the protective role of APN against ROS-induced cardiac remodeling.
authors.affiliation: Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
authors.forename: Eric E
authors.initials: EE
authors.lastname: Essick
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Ouchi
authors.forename: Richard M
authors.initials: RM
authors.lastname: Wilson
authors.forename: Koji
authors.initials: K
authors.lastname: Ohashi
authors.forename: Joanna
authors.initials: J
authors.lastname: Ghobrial
authors.forename: Rei
authors.initials: R
authors.lastname: Shibata
authors.forename: David R
authors.initials: DR
authors.lastname: Pimentel
authors.forename: Flora
authors.initials: F
authors.lastname: Sam
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D052242:Adiponectin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000704:Analysis of Variance; D000804:Angiotensin II; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics / Q000378:metabolism; D006332:Cardiomegaly / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005355:Fibrosis; D017930:Genes, Reporter; D006861:Hydrogen Peroxide / Q000494:pharmacology; D017379:Hypertrophy, Left Ventricular / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D019255:NADPH Oxidases / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D020097:Natriuretic Peptide, Brain / Q000235:genetics / Q000378:metabolism; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D052242:Adiponectin; C499919:Adipoq protein, mouse; D016328:NF-kappa B; D016877:Oxidants; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; D000804:Angiotensin II; D020097:Natriuretic Peptide, Brain; D009320:Atrial Natriuretic Factor; D006861:Hydrogen Peroxide; D019255:NADPH Oxidases; D048049:Extracellular Signal-Regulated MAP Kinases; D055372:AMP-Activated Protein Kinases; D020782:Matrix Metalloproteinases