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European Heart Journal Advance Access published online on November 13, 2008
European Heart Journal, doi:10.1093/eurheartj/ehn482
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

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

Tuomas Peltonen1, Panu Taskinen2, Juha Näpänkangas3, Hanna Leskinen1, Pasi Ohtonen4,5, Ylermi Soini3, Tatu Juvonen2, Jari Satta2, Olli Vuolteenaho6 and Heikki Ruskoaho1,*

1 Department of Pharmacology and Toxicology, Institute of Biomedicine, University of Oulu, Biocenter Oulu, PO Box 5000, Aapistie 5, 90014 Oulu, Finland
2 Department of Cardiovascular Surgery, Oulu University Hospital, Oulu, Finland
3 Department of Pathology, University of Oulu, Oulu, Finland
4 Department of Anaesthesiology, Oulu University Hospital, Oulu, Finland
5 Department of Surgery, Oulu University Hospital, Oulu, Finland
6 Department of Physiology, Biocenter Oulu, University of Oulu, Oulu, Finland

Received 19 February 2008; revised 15 August 2008; accepted 9 October 2008.

* Corresponding author. Tel: +358 8 5375236, Fax: +358 8 5375247, Email: heikki.ruskoaho{at}oulu.fi

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 (ETA) mRNA levels were upregulated in stenotic valves (4.3-fold, P = 0.032) associated with a remarkable increase in number of ETA-immunopositive cells. ETB-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 ETA, promoting growth, inflammation, and fibrosis. These findings suggest therapeutic potential for ETA-receptor antagonists in aortic valve calcification.

Key Words: Aortic valve stenosis • Endothelin-1 • Receptors • Endothelin-converting enzyme • Activator protein-1 • Nitric oxide synthase


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