Abstract 9632: A Functional Role of Tenascin-C in Angiotensin II-Induced Cardiac Fibrosis
Introduction: tenascin-C is sparsely detected in normal adult heart but becomes expressed in the pathological myocardium closely associated with inflammation and tissue remodeling. We have previously reported about enhanced TN-C production and macrophages accumulation in the perivascular fibrosis of angiotensin II (AngII)-induced mouse hypertensive heart.
Hypothesis: The aim of study was to clarify the role of TN-C in progression of hypertensive cardiac fibrosis using TN-C knock-out (TNKO) mouse, and to evaluate whether TN-C is involved in macrophage activation.
Methods: Balb/c WT and TNKO mice (8 week-old) were subcutaneously implanted with an osmotic minipump which released AngII (560 ng/kg body weight/min) for 4 weeks (WT/AngII and TNKO/AngII). In vitro, to test the direct effects of TN-C on macrophage activation, macrophages were isolated from WT mice, seeded in culture well. They were subsequently analyzed using histological and molecular biological approaches.
Results and Conclusions: AngII treatment (WT/AngII and TNKO/AngII) elevated blood pressure, heart weight/body weight ratio, atrial and brain natriuretic peptide expression level and cardiomyocyte size, compared with the saline treatment (WT/Sa and TNKO/Sa). In TNKO/AngII mice, interstitial collagen fibers and accumulation of mac-3 positive macrophages were reduced significantly compared with those of WT/AngII in the perivascular region. Additionally, mRNA expression of interleukin (IL)-6 and monocyte chemoattractant protein (MCP)-1 was decreased. Using an in vitro migration assay, TN-C accelerated macrophage migration in the presence of MCP-1. qRT-PCR analysis demonstrated that TN-C up-regulated IL-6 and MCP-1 mRNA in an NF-κB dependent manner. Interestingly, NF-κB activation and IL-6 mRNA expression were suppressed by integrin αVβ3 antagonist. In heart tissues, Accumulation of integrin αvβ3 and activation of NF-κB in macrophages were confirmed in WT/AngII mice, which are not seen in TNKO/AngII. TN-C accelerates IL-6 production through integrin αVβ3/NF-κB on macrophages and augmenting perivascular inflammation, thereby aggravating fibrosis in a hypertensive heart.
Author Disclosures: N. Shimojo: None. R. Hashizume: None. K. Kanayama: None. Y. Suzuki: None. M. Hara: None. T. Nishioka: None. T. Yoshida: None. K. Imanaka-Yoshida: None.
- © 2014 by American Heart Association, Inc.