Tumor Necrosis Factor-&agr;–Induced AT1Receptor Upregulation Enhances Angiotensin II–Mediated Cardiac Fibroblast Responses That Favor Fibrosis
作者:
JianFeng,
Peng Devorah,
Gurantz Van,
Tran Randy,
Cowling Barry,
期刊:
Circulation Research: Journal of the American Heart Association
(OVID Available online 2002)
卷期:
Volume 91,
issue 12
页码: 1119-1126
ISSN:0009-7330
年代: 2002
出版商: OVID
关键词: collagen synthesis;tumor necrosis factor-&agr;matrix metalloproteinase;tissue inhibitor of matrix metalloproteinase;angiotensin II
数据来源: OVID
摘要:
Abstract—Extracellular matrix (ECM) remodeling after myocardial infarction (MI) is an important determinant of cardiac function. Tumor necrosis factor-&agr; (TNF-&agr;) and angiotensin (Ang) II levels increase after MI and both factors affect fibroblast functions. The type 1 (AT1) receptor that mediates most Ang II effects is upregulated after MI in cardiac fibroblasts, and there is evidence that this is caused by TNF-&agr;. We sought to determine if TNF-&agr;–induced AT1receptor upregulation alters fibroblast responsiveness to Ang II and if this effect differs from direct TNF-&agr; effects on fibroblast functions. In cultured neonatal rat cardiac fibroblasts, TNF-&agr; reduced cellular [3H]-proline incorporation, increased matrix metalloproteinase-2 (MMP-2) activity and protein, and increased TIMP-1 protein levels. In cardiac fibroblasts with TNF-&agr;–induced AT1receptor upregulation, Ang II–stimulated [3H]proline incorporation and TIMP-1 protein production was approximately 2-fold greater than in nonpretreated fibroblasts. Angiotensin II reduced MMP-2 activity and protein level only in TNF-&agr;–pretreated fibroblasts. Angiotensin II effects were inhibited by selective AT1(but not AT2) receptor blockers. Thus, TNF-&agr;–induced AT1receptor upregulation enhances Ang II–mediated functions that favor fibrosis. These effects are mostly directionally opposite of direct TNF-&agr; effects on cardiac fibroblasts. Recognition of multifaceted TNF-&agr; effects provides new insights into post-MI ECM remodeling.
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