Tumor necrosis factor-alpha upregulates angiotensin II type 1 receptors oncardiac fibroblasts

Angiotensin II (Ang II) plays an important role in post-myocardial infarcti on (MI) remodeling. Most Ang II effects related to remodeling involve activ ation of the type 1 receptor (AT(1)), Although the AT(1) receptor is upregu lated on cardiac fibroblasts post-MI, little is known about the mechanisms involved in the process. Consequently, we tested whether growth factors kno wn to be present in the remodeling heart increased AT(1) mRNA levels. Using quantitative competitive reverse transcription-polymerase chain reaction, we found that norepinephrine, endothelin, atrial natriuretic peptide, and b radykinin had no significant effect on AT(1) mRNA levels. Ang II, transform ing growth factor-beta(1), and basic fibroblast growth factor reduced AT(1) mRNA levels (P<0.02). Tumor necrosis factor-alpha (TNF-alpha), however, pr oduced a marked increase in AT(1) mRNA. After 24 hours of TNF-alpha incubat ion, AT1 mRNA increased by 5-fold above control levels (P<0.01). The EC50 f or the TNF-alpha effect was 4.6 ng/mL (0.2 nmol/L), Interleukin (IL)-1 beta caused a 2.4-fold increase, whereas IL-2 and IL-6 had no significant effec t. Studies of TNF-alpha enhancement of AT(1) mRNA levels demonstrate that t he increase was not due to a change in transcript stability. TNF-alpha trea tment for 48 hours also resulted in a 3-fold increase in AT(1) surface rece ptor and a 2-fold increase in Ang II-induced production of inositol phospha tes. The present findings provide evidence for TNF-alpha regulation of AT1 receptor density on cardiac fibroblasts. Because TNF-alpha concentration an d AT(1) receptor density increase in the myocardium after MI, these results raise the possibility that TNF-alpha modulates post-MI remodeling by enhan cing Ang II effects on cardiac fibroblasts.