Increase in tissue endothelin-1 and ETA receptor levels in human aortic valve stenosis

Eur Heart J. 2009 Jan;30(2):242-9. doi: 10.1093/eurheartj/ehn482. Epub 2008 Nov 13.

Abstract

Aims: Aortic valve stenosis (AS) is an actively regulated process like atherosclerosis, which is accompanied by changes e.g. in endothelin-related genes. However, the role of endothelin peptides in AS is unknown.

Methods and results: We characterized the expression of the endothelin system in aortic valves of patients with normal valves (n = 12), regurgitation, and fibrosis (n = 6) and AS (n = 18) by reverse-transcriptase-polymerase chain reaction and immunohistochemistry. The number of endothelin-1 (ET-1) positive cells was higher in AS than in control valves, while levels of ET-1 mRNA did not differ between groups. Endothelin receptor-A (ET(A)) mRNA levels were upregulated in stenotic valves (4.3-fold, P = 0.032) associated with a remarkable increase in number of ET(A)-immunopositive cells. ET(B)-receptor mRNA levels did not change during disease progression. Endothelin-converting enzyme-1 (ECE-1) mRNA levels were 42% lower (P = 0.007) in stenotic valves. Finally, because ET-1 and ECE-1 have binding site for activator protein-1 (AP-1), we measured AP-1 DNA binding by gel shift assays, which showed significantly lower (76%, P = 0.003) activity in AS.

Conclusion: AS is characterized by distinct upregulation of ET-1 and its target receptor ET(A), promoting growth, inflammation, and fibrosis. These findings suggest therapeutic potential for ET(A)-receptor antagonists in aortic valve calcification.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Aortic Valve Stenosis / genetics
  • Aortic Valve Stenosis / metabolism*
  • Aspartic Acid Endopeptidases / genetics*
  • Aspartic Acid Endopeptidases / metabolism
  • Down-Regulation
  • Endothelin-1 / genetics
  • Endothelin-1 / metabolism*
  • Endothelin-Converting Enzymes
  • Female
  • Gene Expression Regulation, Enzymologic
  • Humans
  • Immunohistochemistry
  • Male
  • Metalloendopeptidases / genetics*
  • Metalloendopeptidases / metabolism
  • Middle Aged
  • Nitric Oxide Synthase Type II / metabolism
  • Nitric Oxide Synthase Type III / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptor, Endothelin A / genetics
  • Receptor, Endothelin A / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction

Substances

  • Endothelin-1
  • RNA, Messenger
  • Receptor, Endothelin A
  • Nitric Oxide Synthase Type II
  • Nitric Oxide Synthase Type III
  • Aspartic Acid Endopeptidases
  • Metalloendopeptidases
  • ECE1 protein, human
  • Endothelin-Converting Enzymes