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


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.


CONCLUSIONS
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.
Peltonen
Tuomas
T
Department of Pharmacology and Toxicology, Institute of Biomedicine, University of Oulu, Biocenter Oulu, PO Box 5000, Aapistie 5, 90014 Oulu, Finland.
Taskinen
Panu
P
Näpänkangas
Juha
J
Leskinen
Hanna
H
Ohtonen
Pasi
P
Soini
Ylermi
Y
Juvonen
Tatu
T
Satta
Jari
J
Vuolteenaho
Olli
O
Ruskoaho
Heikki
H
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001024:Aortic Valve Stenosis / Q000235:genetics / Q000378:metabolism*; D016282:Aspartic Acid Endopeptidases / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism*; D000072396:Endothelin-Converting Enzymes; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008666:Metalloendopeptidases / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D044022:Receptor, Endothelin A / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D019332:Endothelin-1; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; C000606923:ECE1 protein, human; D000072396:Endothelin-Converting Enzymes