TRIF/EGFR signalling mediates angiotensin-II-induced cardiac remodelling in mice

in Journal of Molecular Endocrinology
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  • 1 Department of Geriatrics, Xuanwu Hospital, Capital Medical University, Beijing, P.R. China
  • 2 Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, P.R. China
  • 3 Division of Cardiology, Department of Internal Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

Correspondence should be addressed to Y Li: liy_xw@sina.com
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The excessive activation of renin-angiotensin system (RAS) is one of key pathophysiological characteristics in the development of cardiac remodelling. Angiotensin (Ang) II, as a main active peptide in RAS, induces cardiac structural disorders and dysfunction. However, the molecular mechanisms are still not fully disclosed. Present study aimed to determine the role and potential mechanisms of cardiac TIR-domain-containing adapter-inducing interferon-β (TRIF) in Ang-II-mediated cardiac remodelling in mice. In vitro and in vivo studies showed Ang II and downstream aldosterone obviously increased the expression of TRIF, accompanied with cardiac structural abnormalities and functional injuries. Specific blockage of cardiac TRIF effectively decreased Ang-II/aldosterone-induced cardiac inflammation, fibrosis, hypertrophy and dysfunction in mice. Mechanistically, the TRIF triggered the activation of EGF receptor (EGFR) signalling by nuclear factor (NF)-κB transcriptional regulation and downstream EGFR ligands. Taken together, present study supported that cardiac TRIF was a potential therapeutic target for attenuating cardiac pathophysiological remodelling. The TRIF/EGFR axis partially explained the molecular mechanism of Ang-II/aldosterone-induced cardiac inflammation, fibrosis, hypertrophy and dysfunction in mice.

Supplementary Materials

    • Figure S1. The purity of isolated primary mouse cardiomyocytes. Western blot analysis of relative expression of cTnT (cardiomyocyte marker) and α-actinin (fibroblast marker) in isolated primary mouse cardiomyocytes.
    • Figure S2. Cardiac TRIF silence attenuates Ang II-induced cardiac remodelling, but not affects the systolic blood pressure. Male C57BL/6J mice, aged 8 weeks, were locally infused with 1&#x00D7; 1010 lentiviral particles encoding siTrif or siCtrl, and administrated with Ang II (1 &#x03BC;g/kg/min) or saline for 4 weeks. (A-B) Heart sections were stained with Sirius red reagents for cardiac fibrosis (A), and quantitative analysis of relative collagen expression (B). (C) The representative images of echocardiographic analysis. (D) The systolic blood pressure after infusion with Ang II for 0, 2, and 4 weeks. n = 6 mice/group. Results are mean &#x00B1; SEM. **p < 0.01, ***p < 0.001.
    • Figure S3. Suppression of EGFR activity has no effect on the expression of TRIF in Ang II-treated primary mouse cardiomyocytes. (A) Western blot analysis of relative expression of EGFR in primary mouse cardiomyocytes (CMs), endothelial cells (ECs), and circulating monocytes (MCs). (B-C) 1 &#x00D7; 106 primary mouse cardiomyocytes were incubated with 10-7 mol/L Ang II or co-treated with 10-6 mol/L AG1478 for 6 hours. Western blot analysis of TRIF protein level (B) and quantitative analysis of relative TRIF protein level (C) (n = 5 independent experiments). Results are mean &#x00B1; SEM. **p < 0.01.
    • Table S1. Echocardiographic analysis of mouse cardiac parameters after Ang II infusion for 2 weeks.

 

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