Published online before print November 14, 2002, doi: 10.1161/01.RES.0000047090.08299.D5
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Submitted on June 4, 2002
Revised on October 15, 2002
Accepted on November 4, 2002
Tumor Necrosis Factor-
-Induced AT1 Receptor Upregulation Enhances Angiotensin II-Mediated Cardiac Fibroblast Responses That Favor Fibrosis
JianFeng Peng ;
From the Department of Medicine, Division of Cardiology, University of California, San Diego, Calif.
* To whom correspondence should be addressed. E-mail: bgreenberg{at}ucsd.edu.
Extracellular matrix (ECM) remodeling after myocardial infarction (MI) is an important determinant of cardiac function. Tumor necrosis factor-
(TNF-) 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-. We sought to determine if TNF--induced AT1 receptor upregulation alters fibroblast responsiveness to Ang II and if this effect differs from direct TNF- effects on fibroblast functions. In cultured neonatal rat cardiac fibroblasts, TNF- 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--induced AT1 receptor 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--pretreated fibroblasts. Angiotensin II effects were inhibited by selective AT1 (but not AT2) receptor blockers. Thus, TNF--induced AT1 receptor upregulation enhances Ang II-mediated functions that favor fibrosis. These effects are mostly directionally opposite of direct TNF- effects on cardiac fibroblasts. Recognition of multifaceted TNF- effects provides new insights into post-MI ECM remodeling.
Key words: collagen synthesis • tumor necrosis factor-
•
matrix metalloproteinase •
tissue inhibitor of matrix metalloproteinase •
angiotensin II
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