Abstract 385: Tenascin-C Worsens Myocardial Inflammation and Fibrosis by Enhancing Macrophage Activation via NF-kappaB in Mouse Hypertensive Heart

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Background and Aim: Tenascin-C (TN-C) is an extracellular matrix glycoprotein, not detected in normal adult heart but it expresses under various pathological conditions. We have previously reported in the enhanced TN-C production and accumulation of macrophages in the perivascular lesions of angiotensin II (AgII)-induced cardiac fibrosis mouse model. To clarify the role of TN-C in molecular mechanism, we analyzed the effect of TN-C in hypertensive heart utilizing wild-type (WT) and TN-C knock-out (TNKO) mice. Furthermore, to assess whether TN-C is involved in macrophage activation, we investigated in vitro study using macrophages isolated from the peritoneal cavity of WT mice.

Methods and Results: Balb/c WT and TNKO mice were treated with 560 ng/kg body weight/min AgII subcutaneously by osmotic minipump for 4 weeks (WT/AgII and TNKO/AgII), and analyzed histological and molecular biological approaches. AgII treatment increased blood pressure, heart weight/body weight ratio, atrial and brain natriuretic peptide expression level and sizes of cardiomyocytes, but no significant differences were detected between WT/AgII and TNKO/AgII mice. In WT/AgII mice, interstitial collagen fibers (10.29±5.09% vs. WT: 4.6±1.56%, p<0.001) and accumulation of mac-3 positive macrophages (50±15.13 vs. WT: 6±2.55 cells/section, p<0.001) were observed at perivascular regions, and expression levels of interleukin (IL)-6 (1.85±0.39 fold, p<0.05) and monocyte chemoattractant protein (MCP)-1 (3.20±0.53 fold, p<0.001) were up-regulated. These changes were significantly reduced in TNKO/AgII mice. In vitro, TN-C accelerated macrophage migration in the presence of MCP-1. Western blotting and Immunofluorescence staining indicated that TN-C activated rapidly NF-kappaB. RT-PCR analysis demonstrated that TN-C up-regulated IL-6 mRNA on NF-kappaB dependent manner (39.90±18.10 fold, p<0.01). Integrin αVβ3 antagonist P11 suppressed these changes.

Conclusion: The present study clearly demonstrated that TN-C aggravates inflammation and fibrosis in hypertensive heart by upregulation of IL-6 productions by activating NF-kappaB via integrin αVβ3 on macrophage.

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