TY - JOUR
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.
N1 - Funding Information:
We thank Dr Erik Bush and Mr Matthew Jenkin for valuable suggestions to in situ PCR. Part of the content of this article was previously presented in an abstract form (Circulation 1998; 98: I-420). This study was supported by NIH awards HL 03404-03, HL 48013, and HL616401.
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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U2 - 10.1006/jmcc.2002.2022
DO - 10.1006/jmcc.2002.2022
M3 - Article
C2 - 12099722
AN - SCOPUS:18644368829
SN - 0022-2828
VL - 34
SP - 833
EP - 846
JO - Journal of Molecular and Cellular Cardiology
JF - Journal of Molecular and Cellular Cardiology
IS - 7
ER -