[HTML][HTML] Endothelin-1 downregulates Mas receptor expression in human cardiomyocytes

Z Chen, Y Tang, Z Yang, S Liu… - Molecular …, 2013 - spandidos-publications.com
Z Chen, Y Tang, Z Yang, S Liu, Y Liu, Y Li, W He
Molecular medicine reports, 2013spandidos-publications.com
Abstract Endothelin‑1 (ET‑1) and the renin‑angiotensin system (RAS) are involved in the
pathogenesis of cardiac dysfunction. The Mas receptor is a functional binding site for
angiotensin (Ang)‑(1‑7), which is now considered a critical component of the RAS and exerts
cardioprotective effects. To the best of our knowledge, the present study aimed to examine,
for the first time, the effects of ET‑1 on Mas expression in cultured human cardiomyocytes.
Human cardiomyocytes were treated with ET‑1 at different concentrations (1, 5, 10, 20 and …
Abstract
Endothelin‑1 (ET‑1) and the renin‑angiotensin system (RAS) are involved in the pathogenesis of cardiac dysfunction. The Mas receptor is a functional binding site for angiotensin (Ang)‑(1‑7), which is now considered a critical component of the RAS and exerts cardioprotective effects. To the best of our knowledge, the present study aimed to examine, for the first time, the effects of ET‑1 on Mas expression in cultured human cardiomyocytes. Human cardiomyocytes were treated with ET‑1 at different concentrations (1, 5, 10, 20 and 30 nM) for varied time periods (0.5, 1.5, 3, 4.5 or 6 h) with or without the transcription inhibitor actinomycin D, endothelin A (ETA) receptor blocker BQ123 and ETB receptor blocker BQ788, or different kinase inhibitors. ET‑1 decreased the Mas mRNA level in a statistically significant dose-and time‑dependent manner within 4.5 h, which was reflected in the dose‑dependent downregulation of Mas promoter activity, Mas protein levels and Ang‑(1‑7) binding on the cell membrane. Actinomycin D (1 mg/ml), BQ123 (1 µM), p38 mitogen‑activated protein kinase (MAPK) siRNA and inhibitor PD169316 (25 µM), completely eliminated the inhibitory effects of ET‑1 on Mas expression in human cardiomyocytes. In conclusion, the present study demonstrated that ET‑1 downregulates Mas expression at the transcription level in human cardiomyocytes via the ETA receptor by a p38 MAPK‑dependent mechanism. This study provides novel insights into the function of ET‑1 and the Ang‑(1‑7)/Mas axis in cardiac pathophysiology.
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