title: Altered expression of endothelin receptors in failing human left ventricles.
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 (ET(A) and ET(B)) in failing human hearts is not well understood.
  
  
  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 ET(A) ( approximately 60%) and ET(B) ( approximately 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 ET(A) receptor density, to approximately 80% of the total population, and a significant (P<0.02) decrease in ET(B) receptor density. Ribonuclease protection assays demonstrated an increase in ET(A) mRNA abundance in IDC and ISC LVs, and a significant (P<0.04) increase in ET(B) 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 ET(A) gene is expressed in cardiac myocytes, vascular smooth muscle and endothelium; the ET(B) 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, ET(A) receptor density is increased to become the dominant subtype while ET(B) receptor density is decreased. The ET(A), but not the ET(B) 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 ET(A) and ET(B) receptor protein and mRNA expression result from homologous regulation by agonist exposure.
authors.affiliation: Division of Cardiology, The Temple Hoyne Buell Heart Center Research Laboratories, University of Colorado Health Sciences Center, 4200 East Ninth Ave., Denver, CO, 80262, USA.
authors.forename: Koji
authors.initials: K
authors.lastname: Asano
authors.forename: Teresa J
authors.initials: TJ
authors.lastname: Bohlmeyer
authors.forename: Jay Y
authors.initials: JY
authors.lastname: Westcott
authors.forename: Lawrence
authors.initials: L
authors.lastname: Zisman
authors.forename: Koichiro
authors.initials: K
authors.lastname: Kinugawa
authors.forename: Matthew
authors.initials: M
authors.lastname: Good
authors.forename: Wayne A
authors.initials: WA
authors.lastname: Minobe
authors.forename: Robert
authors.initials: R
authors.lastname: Roden
authors.forename: Eugene E
authors.initials: EE
authors.lastname: Wolfel
authors.forename: Joann
authors.initials: J
authors.lastname: Lindenfeld
authors.forename: J
authors.initials: J
authors.lastname: David Port
authors.forename: M Benjamin
authors.initials: MB
authors.lastname: Perryman
authors.forename: Joseph
authors.initials: J
authors.lastname: Clevel
authors.forename: Brian D
authors.initials: BD
authors.lastname: Lowes
authors.forename: Michael R
authors.initials: MR
authors.lastname: Bristow
mesh_terms: D002462:Cell Membrane / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007457:Iodine Radioisotopes; D009206:Myocardium / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D017466:Receptors, Endothelin / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018487:Ventricular Dysfunction, Left / Q000378:metabolism*
chemical_list: D007457:Iodine Radioisotopes; D012333:RNA, Messenger; D017466:Receptors, Endothelin