Abstract 16862: Afterload-Induced Myocardial Fibrosis is Promoted by TRIF-Dependent Inflammation
Background: Inflammation contributes to myocardial and vascular remodeling. The role of TIR-domain-containing adapter-inducing interferon-ß (TRIF) and interferon regulatory factor-3 (IRF3)-dependent inflammatory signaling during myocardial hypertrophy is incompletely understood.
Methods and results: Afterload-induced myocardial remodeling was induced by trans-aortic constriction (TAC) in C57Bl/6J wildtype (WT) and TRIF-/- mice. Left ventricular (LV) mRNA-expression of MyD88-dependent inflammatory cytokines (TNFalpha, IL6) was upregulated 7 days after TAC in both strains, while TRIF-dependent cytokines (CXCL10, CXCL11, RANTES) and pathway molecules (IRF3) remained unchanged in TRIF-/- mice. Furthermore, knockout mice showed reduced CD3 T-cell (8.1±1.3-fold vs. sham, p<0.001) and F4/80 macrophage (10.4±2.0-fold vs. sham, p<0.001) infiltration following TAC, compared to 12.0±2.0-fold (p<0.001), and 24.7±4.0-fold (p<0.001) in WT (p<0.005 TRIF-/- vs. WT). Cytokine levels returned to baseline 5 weeks after TAC. LV hypertrophy (cardiomyocyte size, echocardiography) increased similarly in TRIF-/- (130±6%, p<0.01) and in WT animals (119±3%, p<0.05). Interestingly, capillary density was preserved in TRIF-/- mice 7d after TAC (92±4%, p=ns), but significantly reduced in TAC-WT mice (74±2%, p<0.01 compared to their sham controls). The number of cardiomyocytes/mm² was reduced in WT following TAC (54±6%, p<0.005), but not in TRIF-/- mice (83±1%, p=ns). Instead, myocardial fibrosis was more pronounced in WT 7d following TAC (2.3±0.3% collagen content) than in TRIF-/- mice (1.4±0.2%, p<0.01 TRIF-/- vs. WT), and increase of TGFbeta protein expression was more pronounced in WT (318±85% of sham-operated controls) than in TRIF-/- mice (111±15% of sham-operated controls; p<0.05 TRIF-/- vs. WT). Fibrosis and TGFbeta remained increased after 5 weeks in WT compared to TRIF-/- mice.
Conclusion: TRIF-dependent signaling plays an important role in the regulation of fibrosis and capillarisation during pressure overload-dependent cardiac remodeling in mice. Further studies are ongoing to evaluate particularly diastolic LV function in this model and to investigate molecular effects of TRIF inhibition of fibrogenesis and angiogenesis.
- © 2012 by American Heart Association, Inc.