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(Circulation Research. 2002;91:1119.)
© 2002 American Heart Association, Inc.

Molecular Medicine

Tumor Necrosis Factor-–Induced AT₁ Receptor Upregulation Enhances Angiotensin II–Mediated Cardiac Fibroblast Responses That Favor Fibrosis

JianFeng Peng, Devorah Gurantz, Van Tran, Randy T. Cowling, Barry H. Greenberg

From the Department of Medicine, Division of Cardiology, University of California, San Diego, Calif.

Correspondence to Barry Greenberg, MD, Dept of Medicine/Cardiology, UCSD Medical Center, 200 W Arbor Dr, San Diego, CA 92103-8411. 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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