title: Tezosentan inhibits uptake of proinflammatory endothelin-1 in stenotic aortic valves.
abstract: OBJECTIVE
  Aortic valve stenosis (AS) is an actively regulated pathobiological process which has an inflammation origin, and manifests as an accumulation of lipids and, ultimately, calcification of the aortic valve tissue. Increased plasma levels of the proinflammatory factor endothelin-1 (ET-1) have been reported in AS. Moreover, increased tissue levels of ET-1 and its ET(A) receptor, which mediates the fibrotic and proliferative effects of ET-1, have been reported in stenotic aortic valves. The study aim was to determine whether endothelin receptor antagonism has an effect on the supposed receptor-mediated uptake of ET-1 to aortic valves when ET-1 may be involved in the pathogenesis of AS.
  
  
  METHODS
  By using valve tissue explants in culture, it was determined whether the ET(A)-ET(B) receptor antagonist tezosentan was capable of reducing the uptake of 125I-labeled ET-1 to human aortic valves. Aortic valves were obtained from 16 patients (11 males, five females; mean age 71 +/- 11.2 years) and from two donors without AS (as controls) at the time of aortic valve or aortic root surgery. Valve tissue samples were cultured in ET-1 (10 nmol/l), in the presence or absence of tezosentan (10 nmol/l).
  
  
  RESULTS
  ET-1 uptake was found to be pronounced in the calcified areas of the valve, and tezosentan markedly reduced the receptor-mediated uptake of 125I-labeled ET-1. The inhibitory effect was most evident in the well-calcified part of the valve. The gene expression levels of the ET receptors ET(A) and ET(B) were unaltered in human aortic valves during a four-day exposure to the antagonist.
  
  
  CONCLUSIONS
  The ability of the ET(A)-ET(B) receptor antagonist tezosentan to inhibit ET-1 uptake in valve tissue suggests that continuous ET antagonist therapy might serve as new strategy to slow down the pathophysiological processes of AS.
authors.affiliation: Institute of Biomedicine, Department of Anatomy, University of Oulu, Surgery Clinic, Oulu University Hospital, Finland.
authors.forename: Hannu-Ville
authors.initials: HV
authors.lastname: Leskelä
authors.forename: Olli
authors.initials: O
authors.lastname: Vuolteenaho
authors.forename: Marja-Kaisa
authors.initials: MK
authors.lastname: Koivula
authors.forename: Panu
authors.initials: P
authors.lastname: Taskinen
authors.forename: Heikki
authors.initials: H
authors.lastname: Ruskoaho
authors.forename: Tuomas
authors.initials: T
authors.lastname: Peltonen
authors.forename: Petri
authors.initials: P
authors.lastname: Lehenkari
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001021:Aortic Valve / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001024:Aortic Valve Stenosis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002114:Calcinosis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D058492:Drug Repositioning; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism*; D005260:Female; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D050356:Lipid Metabolism; D008297:Male; D008875:Middle Aged; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D044022:Receptor, Endothelin A / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology / Q000627:therapeutic use; D014665:Vasodilator Agents / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D011725:Pyridines; D044022:Receptor, Endothelin A; D013777:Tetrazoles; D014665:Vasodilator Agents; C120582:tezosentan