IL-1β and TNF-α upregulate angiotensin II type 1 (AT1) receptors on cardiac fibroblasts and are associated with increased AT1 density in the post-MI heart

被引:118
作者
Gurantz, D
Cowling, RT
Varki, N
Frikovsky, E
Moore, CD
Greenberg, BH
机构
[1] Univ Calif San Diego, Med Ctr, Dept Med, Div Cardiol, San Diego, CA 92103 USA
[2] Univ Calif San Diego, Med Ctr, Dept Pathol, San Diego, CA 92103 USA
关键词
AT(1); receptor; cardiac fibroblast; tumor necrosis factor-alpha TNF-alpha; interleukin 1 beta (IL-1 beta); post-myocardial infarction remodeling;
D O I
10.1016/j.yjmcc.2004.12.015
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Angiotensin (Ang) II plays an important role in post-myocardial infarction (MI) cardiac remodeling. The Ang II type I (AT(1)) receptor which mediates most Ang II effects is upregulated on non-myocytes in the post-MI heart. We have shown that pro-inflammatory cytokines increase AT(1) receptor density on cardiac fibroblasts through a mechanism involving NF-kappa B activation. This study examines the in vitro kinetics of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) induced AT(1) receptor upregulation in neonatal rat cardiac fibroblasts and assesses temporal and spatial associations between the appearance of these agents and increased AT(1) receptor density post-MI. The results show that IL-1 beta more rapidly induces AT(1) receptor upregulation than does TNF-alpha, an effect that can be mimicked by a NF-kappa B-dependent luciferase reporter gene. Moreover, the effects of these pro-inflammatory cytokines are additive. Using immunohistochemistry in the post-MI rat heart we found strong temporal and spatial correlations between TNF-alpha, IL-1 beta and AT(1) receptor proteins in the peri-infarction (PI) zone in fibroblasts and macrophages. Labeling intensity for the cytokines and the AT(1) receptor increased from 1 to 7 days post-MI in the PI zone in conjunction with replacement scar formation. This labeling persisted in non-myocytes bordering the scar for up to 83 days post-MI. These findings suggest that IL-1 beta and TNF-alpha act coordinately to increase AT(1) receptor density on non-myocytes in the post-MI heart and that this effect may contribute to extracellular matrix remodeling and fibrosis. (c) 2005 Published by Elsevier Ltd.
引用
收藏
页码:505 / 515
页数:11
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