Endothelin-1 and endothelin-3 regulate endothelin receptor expression in rat coronary arteries
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Endothelin-1 and endothelin-3 regulate endothelin receptor expression in rat coronary arteries. / Skovsted, Gry Freja; Kilic, Semsi; Edvinsson, Lars.
In: Basic & Clinical Pharmacology & Toxicology Online, Vol. 117, No. 5, 2015, p. 297-305.Research output: Contribution to journal › Journal article › Research › peer-review
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T1 - Endothelin-1 and endothelin-3 regulate endothelin receptor expression in rat coronary arteries
AU - Skovsted, Gry Freja
AU - Kilic, Semsi
AU - Edvinsson, Lars
N1 - © 2015 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).
PY - 2015
Y1 - 2015
N2 - 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.
AB - 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.
U2 - 10.1111/bcpt.12407
DO - 10.1111/bcpt.12407
M3 - Journal article
C2 - 25891848
VL - 117
SP - 297
EP - 305
JO - Basic and Clinical Pharmacology and Toxicology
JF - Basic and Clinical Pharmacology and Toxicology
SN - 1742-7835
IS - 5
ER -
ID: 144697335