Endothelin-1 downregulates Mas receptor expression in human cardiomyocytes

Chen,Zhiheng; Tang,Yamei; Yang,Zuocheng; Liu,Shaojun; Liu,Yong; Li,Yan; He,Wei

doi:10.3892/mmr.2013.1577

Endothelin-1 downregulates Mas receptor expression in human cardiomyocytes

Authors:
- Zhiheng Chen
- Yamei Tang
- Zuocheng Yang
- Shaojun Liu
- Yong Liu
- Yan Li
- Wei He
View Affiliations

Affiliations: Department of Pediatrics, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China, Department of Clinical Laboratory, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
Published online on: July 8, 2013 https://doi.org/10.3892/mmr.2013.1577
Pages: 871-876

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

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.

View Figures

View References

1	Domenighetti AA, Wang Q, Egger M, Richards SM, Pedrazzini T and Delbridge LM: Angiotensin II-mediated phenotypic cardiomyocyte remodeling leads to age-dependent cardiac dysfunction and failure. Hypertension. 46:426–432. 2005. View Article : Google Scholar : PubMed/NCBI
2	Mazzolai L, Pedrazzini T, Nicoud F, Gabbiani G, Brunner HR and Nussberger J: Increased cardiac angiotensin II levels induce right and left ventricular hypertrophy in normotensive mice. Hypertension. 35:985–991. 2000. View Article : Google Scholar : PubMed/NCBI
3	Domenighetti AA, Ritchie M, Smyth G, Pedrazzini T, Proietto J and Delbridge LMD: Gene expression profiling reveals distinct sets of genes altered during hormonally and metabolically induced cardiac hypertrophies. J Mol Cell Cardiol. 37:3032004.
4	Ferreira AJ, Murça TM, Fraga-Silva RA, Castro CH, Raizada MK and Santos RA: New cardiovascular and pulmonary therapeutic strategies based on the Angiotensin-converting enzyme 2/angiotensin-(1-7)/mas receptor axis. Int J Hypertens. 2012:1478252012.PubMed/NCBI
5	Raizada MK and Ferreira AJ: ACE2: a new target for cardiovascular disease therapeutics. J Cardiovasc Pharmacol. 50:112–119. 2007. View Article : Google Scholar : PubMed/NCBI
6	Vickers C, Hales P, Kaushik V, et al: Hydrolysis of biological peptides by human angiotensin-converting enzyme-related carboxypeptidase. J Biol Chem. 277:14838–14843. 2002. View Article : Google Scholar : PubMed/NCBI
7	Der Sarkissian S, Huentelman MJ, Stewart J, Katovich MJ and Raizada MK: ACE2: a novel therapeutic target for cardiovascular diseases. Prog Biophys Mol Biol. 91:163–198. 2006.PubMed/NCBI
8	Rice GI, Thomas DA, Grant PJ, Turner AJ and Hooper NM: Evaluation of angiotensin-converting enzyme (ACE), its homologue ACE2 and neprilysin in angiotensin peptide metabolism. Biochem J. 383:45–51. 2004. View Article : Google Scholar : PubMed/NCBI
9	Stanziola L, Greene LJ and Santos RA: Effect of chronic angiotensin converting enzyme inhibition on angiotensin I and bradykinin metabolism in rats. Am J Hypertens. 12:1021–1029. 1999. View Article : Google Scholar : PubMed/NCBI
10	Gomes ER, Santos RA and Guatimosim S: Angiotensin-(1-7)- mediated signaling in cardiomyocytes. Int J Hypertens. 2012:4931292012. View Article : Google Scholar : PubMed/NCBI
11	Ferreira AJ and Santos RA: Cardiovascular actions of angiotensin-(1-7). Braz J Med Biol Res. 38:499–507. 2005. View Article : Google Scholar : PubMed/NCBI
12	Zhang T, Li Z, Dang H, et al: Inhibition of Mas G-protein signaling improves coronary blood flow, reduces myocardial infarct size, and provides long-term cardioprotection. Am J Physiol Heart Circ Physiol. 302:H299–H311. 2012. View Article : Google Scholar : PubMed/NCBI
13	Vignon-Zellweger N, Heiden S, Miyauchi T and Emoto N: Endothelin and endothelin receptors in the renal and cardiovascular systems. Life Sci. 91:490–500. 2012. View Article : Google Scholar : PubMed/NCBI
14	Shichiri M, Hirata Y, Ando K, et al: Plasma endothelin levels in hypertension and chronic renal failure. Hypertension. 15:493–496. 1990. View Article : Google Scholar : PubMed/NCBI
15	Wei CM, Lerman A, Rodeheffer RJ, et al: Endothelin in human congestive heart failure. Circulation. 89:1580–1586. 1994. View Article : Google Scholar : PubMed/NCBI
16	Yazici M, Demircan S, Durna K and Sahin M: The relation between endothelin-1 levels and myocardial injury in chronic ischemic heart failure. Heart Vessels. 20:95–99. 2005. View Article : Google Scholar : PubMed/NCBI
17	Gironacci MM, Adamo HP, Corradi G, Santos RA, Ortiz P and Carretero OA: Angiotensin (1-7) induces MAS receptor internalization. Hypertension. 58:176–181. 2011. View Article : Google Scholar : PubMed/NCBI
18	Windischhofer W, Zach D, Fauler G, Raspotnig G, Köfeler H and Leis HJ: Involvement of Rho and p38 MAPK in endothelin-1-induced expression of PGHS-2 mRNA in osteoblast-like cells. J Bone Miner Res. 17:1774–1784. 2002. View Article : Google Scholar : PubMed/NCBI
19	Ohmae M: Endothelin-1 levels in chronic congestive heart failure. Wien Klin Wochenschr. 123:714–717. 2011. View Article : Google Scholar : PubMed/NCBI
20	Gallagher PE, Ferrario CM and Tallant EA: Regulation of ACE2 in cardiac myocytes and fibroblasts. Am J Physiol Heart Circ Physiol. 295:H2373–H2379. 2008. View Article : Google Scholar : PubMed/NCBI
21	de Jonge HW, Dekkers DH, Houtsmuller AB, Sharma HS and Lamers JM: Differential signaling and hypertrophic responses in cyclically stretched vs endothelin-1 stimulated neonatal rat cardiomyocytes. Cell Biochem Biophys. 47:21–32. 2007.PubMed/NCBI
22	Santos RA, Ferreira AJ, Verano-Braga T and Bader M: Angiotensin-converting enzyme 2, angiotensin-(1-7) and Mas: new players of the renin angiotensin system. J Endocrinol. 216:R1–R17. 2013. View Article : Google Scholar : PubMed/NCBI