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Rapid functional upregulation of vasocontractile endothelin ETB receptors in rat coronary arteries.
Life Sci. 2012 Oct 15; 91(13-14):593-9.LS

Abstract

AIMS

Endothelin ET(B) receptors mediate under normal physiological conditions vasorelaxation in coronary arteries. However, vasocontractile ET(B) receptors appear in coronary arteries of ischemic heart disease patients. Interestingly, organ culture of isolated coronary arteries also induces upregulation of vasocontractile ET(B) receptors. This study examines the early time course and mechanism behind upregulation of contractile ET(B) receptors in isolated rat coronary arteries during short-term organ culture.

MAIN METHODS

Coronary artery segments were mounted in wire-myographs and incubated in physiological saline solution. Contractions were measured after exposure to the specific ET(B) receptor agonist Sarafotoxin 6c (S6c) and the endogenous agonists endothelin-1 and endothelin-3. Protein localization and levels of ET(B) and phosphorylated-extracellular-signal-regulated-kinase-1/2 (ERK1/2) were examined by immunohistochemistry.

KEY FINDINGS

Fresh arteries showed negligible vasoconstriction to S6c. However, incubation for only 4 and 7h increased S6c contractions two- and seven-fold, respectively. Furthermore, 7h incubation enhanced vasocontractile responses to endothelin-3 and increased ET(B) receptor density in vascular smooth muscle cells. ERK1/2 was activated rapidly after start of incubation. Moreover, incubation with either the transcriptional inhibitor actinomycin D or the mitogen-activated-protein kinase kinase 1/2 (MEK1/2) inhibitor U0126 attenuated contractile ET(B) receptor upregulation. U0126 attenuated ET(B) receptor protein levels after 24 h of incubation.

SIGNIFICANCE

Coronary arteries rapidly upregulate vasocontractile ET(B) receptors during organ culture via transcriptional mechanisms and MEK-ERK1/2 signalling. This model may mimic the mechanisms seen in ischemic conditions. Furthermore, these findings have important experimental implications in tissue bath experiments lasting for more than 4h.

Authors+Show Affiliations

Department of Clinical Experimental Research, Glostrup Research Institute, University of Copenhagen, Glostrup Hospital, Ndr. Ringvej 69, DK-2600 Glostrup, Copenhagen, Denmark. grfrsk01@regionh.dkNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

22391414

Citation

Skovsted, Gry Freja, et al. "Rapid Functional Upregulation of Vasocontractile Endothelin ETB Receptors in Rat Coronary Arteries." Life Sciences, vol. 91, no. 13-14, 2012, pp. 593-9.
Skovsted GF, Pedersen AF, Larsen R, et al. Rapid functional upregulation of vasocontractile endothelin ETB receptors in rat coronary arteries. Life Sci. 2012;91(13-14):593-9.
Skovsted, G. F., Pedersen, A. F., Larsen, R., Sheykhzade, M., & Edvinsson, L. (2012). Rapid functional upregulation of vasocontractile endothelin ETB receptors in rat coronary arteries. Life Sciences, 91(13-14), 593-9. https://doi.org/10.1016/j.lfs.2012.02.009
Skovsted GF, et al. Rapid Functional Upregulation of Vasocontractile Endothelin ETB Receptors in Rat Coronary Arteries. Life Sci. 2012 Oct 15;91(13-14):593-9. PubMed PMID: 22391414.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Rapid functional upregulation of vasocontractile endothelin ETB receptors in rat coronary arteries. AU - Skovsted,Gry Freja, AU - Pedersen,Anne Fog, AU - Larsen,Rikke, AU - Sheykhzade,Majid, AU - Edvinsson,Lars, Y1 - 2012/02/25/ PY - 2011/11/02/received PY - 2012/02/01/revised PY - 2012/02/10/accepted PY - 2012/3/7/entrez PY - 2012/3/7/pubmed PY - 2013/1/8/medline SP - 593 EP - 9 JF - Life sciences JO - Life Sci VL - 91 IS - 13-14 N2 - AIMS: Endothelin ET(B) receptors mediate under normal physiological conditions vasorelaxation in coronary arteries. However, vasocontractile ET(B) receptors appear in coronary arteries of ischemic heart disease patients. Interestingly, organ culture of isolated coronary arteries also induces upregulation of vasocontractile ET(B) receptors. This study examines the early time course and mechanism behind upregulation of contractile ET(B) receptors in isolated rat coronary arteries during short-term organ culture. MAIN METHODS: Coronary artery segments were mounted in wire-myographs and incubated in physiological saline solution. Contractions were measured after exposure to the specific ET(B) receptor agonist Sarafotoxin 6c (S6c) and the endogenous agonists endothelin-1 and endothelin-3. Protein localization and levels of ET(B) and phosphorylated-extracellular-signal-regulated-kinase-1/2 (ERK1/2) were examined by immunohistochemistry. KEY FINDINGS: Fresh arteries showed negligible vasoconstriction to S6c. However, incubation for only 4 and 7h increased S6c contractions two- and seven-fold, respectively. Furthermore, 7h incubation enhanced vasocontractile responses to endothelin-3 and increased ET(B) receptor density in vascular smooth muscle cells. ERK1/2 was activated rapidly after start of incubation. Moreover, incubation with either the transcriptional inhibitor actinomycin D or the mitogen-activated-protein kinase kinase 1/2 (MEK1/2) inhibitor U0126 attenuated contractile ET(B) receptor upregulation. U0126 attenuated ET(B) receptor protein levels after 24 h of incubation. SIGNIFICANCE: Coronary arteries rapidly upregulate vasocontractile ET(B) receptors during organ culture via transcriptional mechanisms and MEK-ERK1/2 signalling. This model may mimic the mechanisms seen in ischemic conditions. Furthermore, these findings have important experimental implications in tissue bath experiments lasting for more than 4h. SN - 1879-0631 UR - https://www.unboundmedicine.com/medline/citation/22391414/Rapid_functional_upregulation_of_vasocontractile_endothelin_ETB_receptors_in_rat_coronary_arteries_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0024-3205(12)00080-X DB - PRIME DP - Unbound Medicine ER -