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

被引:98
作者
Gurantz, D [1 ]
Cowling, RT [1 ]
Villarreal, FJ [1 ]
Greenberg, BH [1 ]
机构
[1] Univ Calif San Diego, Med Ctr, Dept Med, Div Cardiol, San Diego, CA 92103 USA
关键词
AT(1); cardiac fibroblast; tumor necrosis factor-alpha; post-myocardial infarction remodeling;
D O I
10.1161/01.RES.85.3.272
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 (AT(1)), Although the AT(1) 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 AT(1) 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 AT(1) mRNA levels. Ang II, transforming growth factor-beta(1), and basic fibroblast growth factor reduced AT(1) mRNA levels (P<0.02). Tumor necrosis factor-alpha (TNF-alpha), however, produced a marked increase in AT(1) mRNA. After 24 hours of TNF-alpha incubation, AT1 mRNA increased by 5-fold above control levels (P<0.01). The EC50 for 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 effect. Studies of TNF-alpha enhancement of AT(1) mRNA levels demonstrate that the increase was not due to a change in transcript stability. TNF-alpha treatment for 48 hours also resulted in a 3-fold increase in AT(1) surface receptor and a 2-fold increase in Ang II-induced production of inositol phosphates. The present findings provide evidence for TNF-alpha regulation of AT1 receptor density on cardiac fibroblasts. Because TNF-alpha concentration and AT(1) receptor density increase in the myocardium after MI, these results raise the possibility that TNF-alpha modulates post-MI remodeling by enhancing Ang II effects on cardiac fibroblasts.
引用
收藏
页码:272 / 279
页数:8
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