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Medical AI Inquiry: You was designed to assist in medical decision-making based on the provided user questions. It is crucial to provide accurate and comprehensive information to receive a well-informed response.  Labels: BACKGROUND, RESULTS. Meshes: Angiotensin II, Animals, Chemokine CX3CL1, Connective Tissue Growth Factor, Gene Expression Regulation, Heart Injuries, Humans, MAP Kinase Signaling System, Matrix Metalloproteinase 14, Matrix Metalloproteinase 2, Matrix Metalloproteinase 9, Mice, Mice, Knockout, Mitogen-Activated Protein Kinase 3, Myocardium, Peptidyl-Dipeptidase A, Phosphorylation, Vasoconstrictor Agents.
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Does loss of angiotensin-converting enzyme 2 exacerbate myocardial injury via activation of the CTGF-fractalkine signaling pathway? Context: 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. 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.
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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. Final Decision: yes