title: C1q/tumor necrosis factor-related protein-9, a novel adipocyte-derived cytokine, attenuates adverse remodeling in the ischemic mouse heart via protein kinase A activation.
abstract: BACKGROUND
  C1q/tumor necrosis factor-related protein-9 (CTRP9) is a newly identified adiponectin paralog with established metabolic regulatory properties. However, the role of CTRP9 in postmyocardial infarction remodeling remains completely unknown. This study determined whether CTRP9 may regulate cardiac remodeling after acute myocardial infarction (AMI) and elucidated the underlying mechanisms.
  
  
  RESULTS
  Male adult mice were subject to AMI by left anterior descending coronary artery ligation or sham surgery and treated with saline (vehicle) or globular CTRP9 via peritoneal implant osmotic pumps for 6 weeks. H9C2 cardiac cell lines were used in vitro for determining underlying mechanisms. Adipocyte CTRP9 expression and plasma CTRP9 levels were both significantly reduced after AMI. Compared with vehicle, CTRP9 treatment improved animal survival rate (P<0.05), restored cardiac function (P<0.05), attenuated adverse remodeling (P<0.01), and ameliorated cardiomyocyte apoptosis and fibrosis after AMI (P<0.01). Among the multiple antiremodeling molecules determined, AMP-activated protein kinase, protein kinase A (PKA), and Akt were significantly activated in CTRP9-treated heart. Surprisingly, CTRP9 remains cardioprotective in mice with cardiomyocyte-specific overexpression of a mutant AMP-activated protein kinase α2 subunit (AMPK-DN). Additional in vitro experiments demonstrated that administration of either PKA inhibitor or PKA-specific small interfering RNA virtually abolished the antiapoptotic effect of CTRP9 (P<0.05), whereas inhibition of Akt is less effective in blocking CTRP9 cardioprotection. Finally, CTRP9 phosphorylates BCL-2-associated agonist of cell death at its multiple antiapoptotic sites, an effect blocked by PKA inhibitor.
  
  
  CONCLUSIONS
  We demonstrate that adipokine CTRP9 attenuates adverse cardiac remodeling after AMI, largely via a PKA-dependent pathway.
authors.affiliation: Departments of Geriatrics (Y.S., H.S., X.W.) and Cardiovascular Surgery (W.Y., D.Y.), Xijing Hospital, the Fourth Military Medical University, Xi'an, China; Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA (Y.S., W.Y., Y.Y., W.B.L., X.W., Y.W., H.S., X.-L.M.); and Center for Translational Medicine, Temple University Medical School, Philadelphia, PA (E.G., W.J.K.).
authors.forename: Yang
authors.initials: Y
authors.lastname: Sun
authors.forename: Wei
authors.initials: W
authors.lastname: Yi
authors.forename: Yuexing
authors.initials: Y
authors.lastname: Yuan
authors.forename: Wayne Bond
authors.initials: WB
authors.lastname: Lau
authors.forename: Dinghua
authors.initials: D
authors.lastname: Yi
authors.forename: Xiaoliang
authors.initials: X
authors.lastname: Wang
authors.forename: Yajing
authors.initials: Y
authors.lastname: Wang
authors.forename: Hui
authors.initials: H
authors.lastname: Su
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Wang
authors.forename: Erhe
authors.initials: E
authors.lastname: Gao
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Koch
authors.forename: Xin-Liang
authors.initials: XL
authors.lastname: Ma
mesh_terms: D017667:Adipocytes / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D054392:Adipokines / Q000502:physiology*; D052242:Adiponectin / Q000008:administration & dosage* / Q000627:therapeutic use; D000818:Animals; D002316:Cardiotonic Agents / Q000008:administration & dosage; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism* / Q000502:physiology; D016207:Cytokines / Q000008:administration & dosage*; D004789:Enzyme Activation / Q000502:physiology; D006023:Glycoproteins / Q000008:administration & dosage* / Q000627:therapeutic use; D015918:Infusion Pumps, Implantable; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017202:Myocardial Ischemia / Q000201:enzymology / Q000378:metabolism* / Q000628:therapy*; D015398:Signal Transduction / Q000502:physiology; D020257:Ventricular Remodeling / Q000502:physiology*
chemical_list: D054392:Adipokines; D052242:Adiponectin; C534692:CTRP9 protein, mouse; D002316:Cardiotonic Agents; D016207:Cytokines; D006023:Glycoproteins; D017868:Cyclic AMP-Dependent Protein Kinases
keywords: adipokines; apoptosis; cardiac remodeling; myocardial infarction
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