title: Cardiomyocyte A Disintegrin And Metalloproteinase 17 (ADAM17) Is Essential in Post-Myocardial Infarction Repair by Regulating Angiogenesis.
abstract: BACKGROUND
  A disintegrin and metalloproteinase 17 (ADAM17) is a membrane-bound enzyme that mediates shedding of many membrane-bound molecules, thereby regulating multiple cellular responses. We investigated the role of cardiomyocyte ADAM17 in myocardial infarction (MI).
  
  
  RESULTS
  Cardiomyocyte-specific ADAM17 knockdown mice (ADAM17(flox/flox)/α-MHC-Cre; f/f/Cre) and parallel controls (ADAM17(flox/flox); f/f) were subjected to MI by ligation of the left anterior descending artery. Post MI, f/f/Cre mice showed compromised survival, higher rates of cardiac rupture, more severe left ventricular dilation, and suppressed ejection fraction compared with parallel f/f-MI mice. Ex vivo ischemic injury (isolated hearts) resulted in comparable recovery in both genotypes. Myocardial vascular density (fluorescent-labeled lectin perfusion and CD31 immunofluorescence staining) was significantly lower in the infarct areas of f/f/Cre-MI compared with f/f-MI mice. Activation of vascular endothelial growth factor receptor 2 (VEGFR2), its mRNA, and total protein levels were reduced in infarcted myocardium in ADAM17 knockdown mice. Transcriptional regulation of VEGFR2 by ADAM17 was confirmed in cocultured cardiomyocyte-fibroblast as ischemia-induced VEGFR2 expression was blocked by ADAM17-siRNA. Meanwhile, ADAM17-siRNA did not alter VEGFA bioavailability in the conditioned media. ADAM17 knockdown mice (f/f/Cre-MI) exhibited reduced nuclear factor-κB activation (DNA binding) in the infarcted myocardium, which could underlie the suppressed VEGFR2 expression in these hearts. Post MI, inflammatory response was not altered by ADAM17 downregulation.
  
  
  CONCLUSIONS
  This study highlights the key role of cardiomyocyte ADAM17 in post-MI recovery by regulating VEGFR2 transcription and angiogenesis, thereby limiting left ventricular dilation and dysfunction. Therefore, ADAM17 upregulation, within the physiological range, could provide protective effects in ischemic cardiomyopathy.
authors.affiliation: From the Department of Physiology (D.F., A.T., M.S., X.W., Z.K.), Division of Cardiology, Department of Medicine (W.W., R.B., G.Y.O.), Cardiovascular Research Center (D.F., A.T., M.S., X.W., Z.K., W.W., R.B.), Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Dong
authors.initials: D
authors.lastname: Fan
authors.affiliation: From the Department of Physiology (D.F., A.T., M.S., X.W., Z.K.), Division of Cardiology, Department of Medicine (W.W., R.B., G.Y.O.), Cardiovascular Research Center (D.F., A.T., M.S., X.W., Z.K., W.W., R.B.), Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Abhijit
authors.initials: A
authors.lastname: Takawale
authors.affiliation: From the Department of Physiology (D.F., A.T., M.S., X.W., Z.K.), Division of Cardiology, Department of Medicine (W.W., R.B., G.Y.O.), Cardiovascular Research Center (D.F., A.T., M.S., X.W., Z.K., W.W., R.B.), Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Mengcheng
authors.initials: M
authors.lastname: Shen
authors.affiliation: From the Department of Physiology (D.F., A.T., M.S., X.W., Z.K.), Division of Cardiology, Department of Medicine (W.W., R.B., G.Y.O.), Cardiovascular Research Center (D.F., A.T., M.S., X.W., Z.K., W.W., R.B.), Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Wang
authors.initials: W
authors.lastname: Wang
authors.affiliation: From the Department of Physiology (D.F., A.T., M.S., X.W., Z.K.), Division of Cardiology, Department of Medicine (W.W., R.B., G.Y.O.), Cardiovascular Research Center (D.F., A.T., M.S., X.W., Z.K., W.W., R.B.), Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Xiuhua
authors.initials: X
authors.lastname: Wang
authors.affiliation: From the Department of Physiology (D.F., A.T., M.S., X.W., Z.K.), Division of Cardiology, Department of Medicine (W.W., R.B., G.Y.O.), Cardiovascular Research Center (D.F., A.T., M.S., X.W., Z.K., W.W., R.B.), Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Ratnadeep
authors.initials: R
authors.lastname: Basu
authors.affiliation: From the Department of Physiology (D.F., A.T., M.S., X.W., Z.K.), Division of Cardiology, Department of Medicine (W.W., R.B., G.Y.O.), Cardiovascular Research Center (D.F., A.T., M.S., X.W., Z.K., W.W., R.B.), Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Gavin Y
authors.initials: GY
authors.lastname: Oudit
authors.affiliation: From the Department of Physiology (D.F., A.T., M.S., X.W., Z.K.), Division of Cardiology, Department of Medicine (W.W., R.B., G.Y.O.), Cardiovascular Research Center (D.F., A.T., M.S., X.W., Z.K., W.W., R.B.), Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada. z.kassiri@ualberta.ca.
authors.forename: Zamaneh
authors.initials: Z
authors.lastname: Kassiri
mesh_terms: D051722:ADAM Proteins / Q000096:biosynthesis / Q000235:genetics*; D000072198:ADAM17 Protein; D000818:Animals; D003326:Coronary Circulation / Q000235:genetics*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation; D051379:Mice; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000378:metabolism; D012313:RNA / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha; D020257:Ventricular Remodeling
chemical_list: D014409:Tumor Necrosis Factor-alpha; D012313:RNA; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse
keywords: cardiac remodeling; inflammation; myocardial infarction; tumor necrosis factor-alpha convertase; vascular endothelial growth factor receptor-2