In cultured neonatal rat cardiac fibroblasts, TNF-alpha-induced AT1 receptor upregulation enhanced Ang II-stimulated [3H]proline incorporation and TIMP-1 production by approximately 2-fold.
Does TNF-alpha-induced AT1 receptor upregulation alter fibroblast responsiveness to Ang II in cultured neonatal rat cardiac fibroblasts?
TNF-alpha-induced AT1 receptor upregulation enhances Ang II-mediated functions that favor fibrosis in cardiac fibroblasts, providing insights into post-MI ECM remodeling.
Effect estimate: ~2-fold greater
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 (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-alpha. We sought to determine if TNF-alpha-induced AT1 receptor upregulation alters fibroblast responsiveness to Ang II and if this effect differs from direct TNF-alpha effects on fibroblast functions. In cultured neonatal rat cardiac fibroblasts, TNF-alpha 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-alpha-induced AT1 receptor upregulation, Ang II-stimulated 3Hproline 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 AT1 (but not AT2) receptor blockers. Thus, TNF-alpha-induced AT1 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.
Peng et al. (Fri,) conducted a other in Myocardial infarction (in vitro model). TNF-alpha pretreatment and Angiotensin II vs. Nonpretreated fibroblasts was evaluated on Ang II-stimulated [3H]proline incorporation and TIMP-1 protein production (~2-fold greater). In cultured neonatal rat cardiac fibroblasts, TNF-alpha-induced AT1 receptor upregulation enhanced Ang II-stimulated [3H]proline incorporation and TIMP-1 production by approximately 2-fold.