Altered expression of endothelin receptors in failing human left ventricles

Koji Asano, Teresa J. Bohlmeyer, Jay Y. Westcott, Lawrence Zisman, Koichiro Kinugawa, Matthew Good, Wayne A. Minobe, Robert Roden, Eugene E. Wolfel, Joann Lindenfeld, J. David Port, M. Benjamin Perryman, Joseph Clevel, Brian D. Lowes, Michael R. Bristow

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

Background: Endothelin signaling is activated in failing human hearts, and may contribute to progressive myocardial dysfunction and remodeling. However, the behavior of endothelin receptor systems (ETA and ETB) in failing human hearts is not well understood. Methods and Results: 125[I]-endothelin-1 binding assays conducted in the presence of a non-hydrolyzable guanine nucleotide to uncouple agonist binding demonstrated that membranes prepared from nonfailing left ventricles (LVs) exhibit a mixed pattern of ETA (∼60%) and ETB (∼40%) receptor protein expression. Chronic LV failure from either idiopathic dilated (IDC) or ischemic (ISC) cardiomyopathy was accompanied by a significant (P < 0.001) increase in ETA receptor density, to ∼80% of the total population, and a significant (P < 0.02) decrease in ETB receptor density. Ribonuclease protection assays demonstrated an increase in ETA mRNA abundance in IDC and ISC LVs, and a significant (P < 0.04) increase in ETB mRNA abundance in ISC LVs. Enzyme-linked immunoabsorbent assays demonstrated a significant increase in tissue immunoreactive endothelin-1 concentration in IDC (P = 0.01) and in IDC + ISC LVs (P = 0.02), but receptor subtype protein or mRNA level was not significantly correlated with tissue ET-1 across all LVs. In situ reverse-transcription polymerase chain reaction in LV sections demonstrated that in both failing and nonfailing LVs the ETA gene is expressed in cardiac myocytes, vascular smooth muscle and endothelium; the ETB gene is expressed in cardiac myocytes, fibroblasts and endothelium; and the prepro-endothelin-1 gene is expressed in myocytes and interstitial cells. Conclusions: In chronically failing human LVs. ETA receptor density is increased to become the dominant subtype while ETB receptor density is decreased. The ETA, but not the ETB density change is accompanied by cognate regulation of mRNA abundance. Both receptor genes and prepro-endothelin-1 are expressed in cardiac myocytes. Finally, based on a lack of correlation with endothelin-1 tissue levels, it is unlikely that the failure-related changes in ETA and ETB receptor protein and mRNA expression result from homologous regulation by agonist exposure.

Original languageEnglish (US)
Pages (from-to)833-846
Number of pages14
JournalJournal of Molecular and Cellular Cardiology
Volume34
Issue number7
DOIs
StatePublished - Jul 1 2002

Fingerprint

Endothelin Receptors
Heart Ventricles
Endothelin-1
Messenger RNA
Cardiac Myocytes
Genes
Endothelium
Proteins
Guanine Nucleotides
Endothelins
Ribonucleases
Cardiomyopathies
Vascular Smooth Muscle
Muscle Cells
Reverse Transcription
Fibroblasts
Polymerase Chain Reaction
Membranes

Keywords

  • Endothelin
  • Endothelin receptor gene expression
  • Heart failure
  • In situ polymerase chain reaction

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

Cite this

Asano, K., Bohlmeyer, T. J., Westcott, J. Y., Zisman, L., Kinugawa, K., Good, M., ... Bristow, M. R. (2002). Altered expression of endothelin receptors in failing human left ventricles. Journal of Molecular and Cellular Cardiology, 34(7), 833-846. https://doi.org/10.1006/jmcc.2002.2022

Altered expression of endothelin receptors in failing human left ventricles. / Asano, Koji; Bohlmeyer, Teresa J.; Westcott, Jay Y.; Zisman, Lawrence; Kinugawa, Koichiro; Good, Matthew; Minobe, Wayne A.; Roden, Robert; Wolfel, Eugene E.; Lindenfeld, Joann; David Port, J.; Perryman, M. Benjamin; Clevel, Joseph; Lowes, Brian D.; Bristow, Michael R.

In: Journal of Molecular and Cellular Cardiology, Vol. 34, No. 7, 01.07.2002, p. 833-846.

Research output: Contribution to journalArticle

Asano, K, Bohlmeyer, TJ, Westcott, JY, Zisman, L, Kinugawa, K, Good, M, Minobe, WA, Roden, R, Wolfel, EE, Lindenfeld, J, David Port, J, Perryman, MB, Clevel, J, Lowes, BD & Bristow, MR 2002, 'Altered expression of endothelin receptors in failing human left ventricles', Journal of Molecular and Cellular Cardiology, vol. 34, no. 7, pp. 833-846. https://doi.org/10.1006/jmcc.2002.2022
Asano, Koji ; Bohlmeyer, Teresa J. ; Westcott, Jay Y. ; Zisman, Lawrence ; Kinugawa, Koichiro ; Good, Matthew ; Minobe, Wayne A. ; Roden, Robert ; Wolfel, Eugene E. ; Lindenfeld, Joann ; David Port, J. ; Perryman, M. Benjamin ; Clevel, Joseph ; Lowes, Brian D. ; Bristow, Michael R. / Altered expression of endothelin receptors in failing human left ventricles. In: Journal of Molecular and Cellular Cardiology. 2002 ; Vol. 34, No. 7. pp. 833-846.
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abstract = "Background: Endothelin signaling is activated in failing human hearts, and may contribute to progressive myocardial dysfunction and remodeling. However, the behavior of endothelin receptor systems (ETA and ETB) in failing human hearts is not well understood. Methods and Results: 125[I]-endothelin-1 binding assays conducted in the presence of a non-hydrolyzable guanine nucleotide to uncouple agonist binding demonstrated that membranes prepared from nonfailing left ventricles (LVs) exhibit a mixed pattern of ETA (∼60{\%}) and ETB (∼40{\%}) receptor protein expression. Chronic LV failure from either idiopathic dilated (IDC) or ischemic (ISC) cardiomyopathy was accompanied by a significant (P < 0.001) increase in ETA receptor density, to ∼80{\%} of the total population, and a significant (P < 0.02) decrease in ETB receptor density. Ribonuclease protection assays demonstrated an increase in ETA mRNA abundance in IDC and ISC LVs, and a significant (P < 0.04) increase in ETB mRNA abundance in ISC LVs. Enzyme-linked immunoabsorbent assays demonstrated a significant increase in tissue immunoreactive endothelin-1 concentration in IDC (P = 0.01) and in IDC + ISC LVs (P = 0.02), but receptor subtype protein or mRNA level was not significantly correlated with tissue ET-1 across all LVs. In situ reverse-transcription polymerase chain reaction in LV sections demonstrated that in both failing and nonfailing LVs the ETA gene is expressed in cardiac myocytes, vascular smooth muscle and endothelium; the ETB gene is expressed in cardiac myocytes, fibroblasts and endothelium; and the prepro-endothelin-1 gene is expressed in myocytes and interstitial cells. Conclusions: In chronically failing human LVs. ETA receptor density is increased to become the dominant subtype while ETB receptor density is decreased. The ETA, but not the ETB density change is accompanied by cognate regulation of mRNA abundance. Both receptor genes and prepro-endothelin-1 are expressed in cardiac myocytes. Finally, based on a lack of correlation with endothelin-1 tissue levels, it is unlikely that the failure-related changes in ETA and ETB receptor protein and mRNA expression result from homologous regulation by agonist exposure.",
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T1 - Altered expression of endothelin receptors in failing human left ventricles

AU - Asano, Koji

AU - Bohlmeyer, Teresa J.

AU - Westcott, Jay Y.

AU - Zisman, Lawrence

AU - Kinugawa, Koichiro

AU - Good, Matthew

AU - Minobe, Wayne A.

AU - Roden, Robert

AU - Wolfel, Eugene E.

AU - Lindenfeld, Joann

AU - David Port, J.

AU - Perryman, M. Benjamin

AU - Clevel, Joseph

AU - Lowes, Brian D.

AU - Bristow, Michael R.

PY - 2002/7/1

Y1 - 2002/7/1

N2 - Background: Endothelin signaling is activated in failing human hearts, and may contribute to progressive myocardial dysfunction and remodeling. However, the behavior of endothelin receptor systems (ETA and ETB) in failing human hearts is not well understood. Methods and Results: 125[I]-endothelin-1 binding assays conducted in the presence of a non-hydrolyzable guanine nucleotide to uncouple agonist binding demonstrated that membranes prepared from nonfailing left ventricles (LVs) exhibit a mixed pattern of ETA (∼60%) and ETB (∼40%) receptor protein expression. Chronic LV failure from either idiopathic dilated (IDC) or ischemic (ISC) cardiomyopathy was accompanied by a significant (P < 0.001) increase in ETA receptor density, to ∼80% of the total population, and a significant (P < 0.02) decrease in ETB receptor density. Ribonuclease protection assays demonstrated an increase in ETA mRNA abundance in IDC and ISC LVs, and a significant (P < 0.04) increase in ETB mRNA abundance in ISC LVs. Enzyme-linked immunoabsorbent assays demonstrated a significant increase in tissue immunoreactive endothelin-1 concentration in IDC (P = 0.01) and in IDC + ISC LVs (P = 0.02), but receptor subtype protein or mRNA level was not significantly correlated with tissue ET-1 across all LVs. In situ reverse-transcription polymerase chain reaction in LV sections demonstrated that in both failing and nonfailing LVs the ETA gene is expressed in cardiac myocytes, vascular smooth muscle and endothelium; the ETB gene is expressed in cardiac myocytes, fibroblasts and endothelium; and the prepro-endothelin-1 gene is expressed in myocytes and interstitial cells. Conclusions: In chronically failing human LVs. ETA receptor density is increased to become the dominant subtype while ETB receptor density is decreased. The ETA, but not the ETB density change is accompanied by cognate regulation of mRNA abundance. Both receptor genes and prepro-endothelin-1 are expressed in cardiac myocytes. Finally, based on a lack of correlation with endothelin-1 tissue levels, it is unlikely that the failure-related changes in ETA and ETB receptor protein and mRNA expression result from homologous regulation by agonist exposure.

AB - Background: Endothelin signaling is activated in failing human hearts, and may contribute to progressive myocardial dysfunction and remodeling. However, the behavior of endothelin receptor systems (ETA and ETB) in failing human hearts is not well understood. Methods and Results: 125[I]-endothelin-1 binding assays conducted in the presence of a non-hydrolyzable guanine nucleotide to uncouple agonist binding demonstrated that membranes prepared from nonfailing left ventricles (LVs) exhibit a mixed pattern of ETA (∼60%) and ETB (∼40%) receptor protein expression. Chronic LV failure from either idiopathic dilated (IDC) or ischemic (ISC) cardiomyopathy was accompanied by a significant (P < 0.001) increase in ETA receptor density, to ∼80% of the total population, and a significant (P < 0.02) decrease in ETB receptor density. Ribonuclease protection assays demonstrated an increase in ETA mRNA abundance in IDC and ISC LVs, and a significant (P < 0.04) increase in ETB mRNA abundance in ISC LVs. Enzyme-linked immunoabsorbent assays demonstrated a significant increase in tissue immunoreactive endothelin-1 concentration in IDC (P = 0.01) and in IDC + ISC LVs (P = 0.02), but receptor subtype protein or mRNA level was not significantly correlated with tissue ET-1 across all LVs. In situ reverse-transcription polymerase chain reaction in LV sections demonstrated that in both failing and nonfailing LVs the ETA gene is expressed in cardiac myocytes, vascular smooth muscle and endothelium; the ETB gene is expressed in cardiac myocytes, fibroblasts and endothelium; and the prepro-endothelin-1 gene is expressed in myocytes and interstitial cells. Conclusions: In chronically failing human LVs. ETA receptor density is increased to become the dominant subtype while ETB receptor density is decreased. The ETA, but not the ETB density change is accompanied by cognate regulation of mRNA abundance. Both receptor genes and prepro-endothelin-1 are expressed in cardiac myocytes. Finally, based on a lack of correlation with endothelin-1 tissue levels, it is unlikely that the failure-related changes in ETA and ETB receptor protein and mRNA expression result from homologous regulation by agonist exposure.

KW - Endothelin

KW - Endothelin receptor gene expression

KW - Heart failure

KW - In situ polymerase chain reaction

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