期刊
CIRCULATION RESEARCH
卷 91, 期 12, 页码 1119-1126出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/01.RES.0000047090.08299.D5
关键词
collagen synthesis; tumor necrosis factor-alpha; matrix metalloproteinase; tissue inhibitor of matrix metalloproteinase angiotensin II
资金
- NHLBI NIH HHS [R01 HL63909] Funding Source: Medline
Extracellular matrix (ECM) remodeling after myocardial infarction (MI) is an important determinant of cardiac function. Tumor necrosis factor-alpha (TNF-alpha) and angiotensin (Ang) II levels increase after MI and both factors affect fibroblast functions. The type 1 (AT(1)) receptor that mediates most Ang II effects is upregulated after MI in cardiac fibroblasts, and there is evidence that this is caused by TNF-alpha. We sought to determine if TNF-alpha-induced AT(1) receptor upregulation alters fibroblast responsiveness to Ang II and if this effect differs from direct TNF-a effects on fibroblast functions. In cultured neonatal rat cardiac fibroblasts, TNF-alpha reduced cellular [H-3]-proline incorporation, increased matrix metalloproteinase-2 (MMP-2) activity and protein, and increased TIMP-1 protein levels. In cardiac fibroblasts with TNF-alpha-induced AT(1) receptor upregulation, Ang II-stimulated [H-3]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-alpha-pretreated fibroblasts. Angiotensin II effects were inhibited by selective AT(1) (but not AT(2)) receptor blockers. Thus, TNF-alpha-induced AT(1) receptor upregulation enhances Ang II-mediated functions that favor fibrosis. These effects are mostly directionally opposite of direct TNF-alpha effects on cardiac fibroblasts. Recognition of multifaceted TNF-alpha effects provides new insights into post-MI ECM remodeling.
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