Endothelin-1 and Endothelin-3 Regulate Endothelin Receptor Expression in Rat Coronary Arteries

Basic Clin Pharmacol Toxicol. 2015 Nov;117(5):297-305. doi: 10.1111/bcpt.12407. Epub 2015 May 18.

Abstract

In ischaemic hearts, endothelin (ET) levels are increased, and vasoconstrictor responses to ET-1 are greatly enhanced. We previously reported that ETB receptors are up-regulated in the smooth muscle layer of coronary arteries after myocardial ischaemia-reperfusion and that the MEK-ERK1/2 signalling pathway is involved in ETB receptor up-regulation. Whether ETs are directly involved in receptor regulation has not been determined. We suggest that ET-1 and ET-3 alter the expression/activity of ET receptors in coronary vascular smooth muscle cells. Vasoconstrictor responses were studied in endothelium-denuded coronary artery segments from rats that were subjected to experimental ischaemia-reperfusion or in organ-cultured segments. Post-ischaemic and cultured coronary arteries exhibited similar increased sensitivity to ET-3. ETA receptor-mediated vasoconstriction was dominant in fresh and non-ischaemic arteries. Organ culture significantly up-regulated ETB receptors and down-regulated ETA receptor expression. Co-incubation with ET-1 (1 nM) or ET-3 (100 nM) induced further down-regulation of the ETA receptor mRNA, while the function and protein level of ETA remained unchanged. ET-3 (100 nM) further up-regulated ETB receptor mRNA and proteins but abolished ETB receptor-mediated vasoconstriction, suggesting a desensitization of ETB receptors that was not observed with ET-3 (1 nM). In conclusion, ET-1, which is the most prevalent isoform in the cardiovascular system, induces down-regulation of ETA receptor expression without changing ETA or ETB receptor function or protein levels. Intermediate concentrations of ET-3 had an effect that was similar to that of ET-1, such that high concentrations of ET-3 (100 nM) up-regulated the ETB receptor at the gene and protein levels but switched off the function of the ETB receptors via desensitization.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Coronary Vessels / drug effects*
  • Coronary Vessels / metabolism
  • Coronary Vessels / physiopathology
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Endothelin-1 / pharmacology*
  • Endothelin-3 / pharmacology*
  • Gene Expression Regulation
  • Humans
  • Myocardial Infarction / genetics
  • Myocardial Infarction / metabolism*
  • Myocardial Infarction / physiopathology
  • Myocardial Reperfusion Injury / genetics
  • Myocardial Reperfusion Injury / metabolism*
  • Myocardial Reperfusion Injury / physiopathology
  • Organ Culture Techniques
  • RNA, Messenger / metabolism
  • Rats, Sprague-Dawley
  • Receptor, Endothelin A / agonists*
  • Receptor, Endothelin A / genetics
  • Receptor, Endothelin A / metabolism
  • Receptor, Endothelin B / agonists*
  • Receptor, Endothelin B / genetics
  • Receptor, Endothelin B / metabolism
  • Time Factors
  • Vasoconstriction / drug effects
  • Vasoconstrictor Agents / pharmacology*

Substances

  • Endothelin-1
  • Endothelin-3
  • RNA, Messenger
  • Receptor, Endothelin A
  • Receptor, Endothelin B
  • Vasoconstrictor Agents