Tumor necrosis factor-α upregulates angiotensin II type 1 receptors on cardiac fibroblasts

Abstract

Angiotensin II (Ang II) plays an important role in post-myocardial infarction (MI) remodeling. Most Ang II effects related to remodeling involve activation of the type 1 receptor (AT1). Although the AT1 receptor is upregulated on cardiac fibroblasts post-MI, little is known about the mechanisms involved in the process. Consequently, we tested whether growth factors known to be present in the remodeling heart increased AT1 mRNA levels. Using quantitative competitive reverse transcription-polymerase chain reaction, we found that norepinephrine, endothelin, atrial natriuretic peptide, and bradykinin had no significant effect on AT1 mRNA levels. Ang II, transforming growth factor-β1, and basic fibroblast growth factor reduced AT1 mRNA levels (P<0.02). Tumor necrosis factor-α (TNF-α), however, produced a marked increase in AT1 mRNA. After 24 hours of TNF-α incubation, AT1 mRNA increased by 5-fold above control levels (P<0.01). The EC50 for the TNF-α effect was 4.6 ng/mL (0.2 nmol/L). Interleukin (IL)- 1β caused a 2.4-fold increase, whereas IL-2 and IL-6 had no significant effect. Studies of TNF-α enhancement of AT1 mRNA levels demonstrate that the increase was not due to a change in transcript stability. TNF-α treatment for 48 hours also resulted in a 3-fold increase in AT1 surface receptor and a 2-fold increase in Ang II-induced production of inositol phosphates. The present findings provide evidence for TNF-α regulation of AT1 receptor density on cardiac fibroblasts. Because TNF-α concentration and AT1 receptor density increase in the myocardium after MI, these results raise the possibility that TNF-α modulates post-MI remodeling by enhancing Ang II effects on cardiac fibroblasts.