title: Loss of angiotensin-converting enzyme 2 exacerbates myocardial injury via activation of the CTGF-fractalkine signaling pathway.
abstract: BACKGROUND
  Angiotensin-converting enzyme 2 (ACE2) has been implicated in human heart failure, but the mechanism remains elusive. We hypothesized that ACE2 deficiency would exacerbate angiotensin (Ang) II-mediated myocardial injury.
  
  
  RESULTS
  10-week-old ACE2 knockout (ACE2KO) and wild-type mice received by mini-osmotic pump either AngII (1.5 mg·kg(-1)·day(-1)) or saline for 2 weeks. ACE2 deficiency triggered greater increases in the expression of connective tissue growth factor (CTGF), fractalkine (FKN) and phosphorylated ERK1/2 in AngII-treated ACE2KO hearts. These changes were associated with greater activation of matrix metalloproteinase (MMP) 2, MMP9 and MT1-MMP and exacerbation of myocardial injury and dysfunction. In cultured cardiofibroblasts, exposure to AngII (100 nmol/L) for 30 min resulted in marked increases in superoxide production and expression of CTGF, FKN and phosphorylated ERK1/2, which were strikingly prevented by recombinant human ACE2 (rhACE2; 1mg/ml) and the CTGF-neutralizing antibody (5 μg/ml), but were aggravated by ACE2 inhibitor DX600 (0.5 μmol/L). These protective effects of rhACE2 were eradicated by the Ang-(1-7) antagonist A779 (1 μmol/L). More intriguingly, rhACE2 treatment significantly abolished AngII-mediated increases in MMP2, MMP9 and MT1-MMP in cardiofibroblasts.
  
  
  CONCLUSIONS
  Loss of ACE2 exacerbates AngII-mediated inflammation, myocardial injury and dysfunction in ACE2-deficient hearts via activation of the CTGF-FKN-ERK and MMP signaling. ACE2 gene may represent a potential candidate to prevent and treat myocardial injury and heart diseases.
authors.affiliation: State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine.
authors.forename: Bei
authors.initials: B
authors.lastname: Song
authors.forename: Zhen-Zhou
authors.initials: ZZ
authors.lastname: Zhang
authors.forename: Jiu-Chang
authors.initials: JC
authors.lastname: Zhong
authors.forename: Xi-Yong
authors.initials: XY
authors.lastname: Yu
authors.forename: Gavin Y
authors.initials: GY
authors.lastname: Oudit
authors.forename: Hai-Yan
authors.initials: HY
authors.lastname: Jin
authors.forename: Lin
authors.initials: L
authors.lastname: Lu
authors.forename: Ying-Le
authors.initials: YL
authors.lastname: Xu
authors.forename: Zamaneh
authors.initials: Z
authors.lastname: Kassiri
authors.forename: Wei-Feng
authors.initials: WF
authors.lastname: Shen
authors.forename: Ping-Jin
authors.initials: PJ
authors.lastname: Gao
authors.forename: Ding-Liang
authors.initials: DL
authors.lastname: Zhu
mesh_terms: D000804:Angiotensin II / Q000009:adverse effects / Q000494:pharmacology; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D054428:Chemokine CX3CL1 / Q000096:biosynthesis* / Q000235:genetics; D055513:Connective Tissue Growth Factor / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006335:Heart Injuries / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D020935:MAP Kinase Signaling System; D053511:Matrix Metalloproteinase 14 / Q000096:biosynthesis / Q000235:genetics; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis / Q000235:genetics; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D014662:Vasoconstrictor Agents / Q000009:adverse effects / Q000494:pharmacology
chemical_list: C526318:CCN2 protein, mouse; D054428:Chemokine CX3CL1; C515539:Cx3cl1 protein, mouse; C507096:Mmp14 protein, mouse; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D055513:Connective Tissue Growth Factor; D048052:Mitogen-Activated Protein Kinase 3; D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; D053511:Matrix Metalloproteinase 14