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(Circulation. 2007;116:1283-1289.)
© 2007 American Heart Association, Inc.

Valvular Heart Disease

Distinct Downregulation of C-Type Natriuretic Peptide System in Human Aortic Valve Stenosis

Tuomas O. Peltonen, MD; Panu Taskinen, MD, PhD; Ylermi Soini, MD, PhD; Jaana Rysä, MSc; Jarkko Ronkainen, MD; Pasi Ohtonen, MSc; Jari Satta, MD, PhD; Tatu Juvonen, MD, PhD; Heikki Ruskoaho, MD, PhD; Hanna Leskinen, MD, PhD

From the Department of Pharmacology and Toxicology (T.O.P., J. Rysä, H.R., H.L.) and Department of Physiology (J. Ronkainen), Biocenter Oulu, and the Department of Pathology (Y.S.), University of Oulu, Oulu, Finland; and the Department of Cardiovascular Surgery (P.T., J.S., T.J.) and Departments of Anaesthesiology and Surgery (P.O.), Oulu University Hospital, Oulu, Finland.

Correspondence to Heikki Ruskoaho, Department of Pharmacology and Toxicology, University of Oulu, PO Box 5000, 90014 Oulu, Finland. E-mail heikki.ruskoaho{at}oulu.fi

Received December 22, 2006; accepted July 9, 2007.

Background— Aortic valve calcification is an actively regulated process that displays hallmarks of atherosclerosis. Natriuretic peptides (A-, B-, and C-type natriuretic peptides [ANP, BNP, and CNP]) have been reported to have a role in the pathogenesis of vascular atherosclerosis, but their expression in aortic valves is not known. Here, we characterized and compared expression of natriuretic peptide system in aortic valves of patients with normal valves (n=4), aortic regurgitation (n=11), regurgitation and fibrosis (n=6), and aortic valve stenosis (n=21).

Methods and Results— By reverse-transcription polymerase chain reaction, all 3 natriuretic peptides were found to be expressed in aortic valves. CNP mRNA levels were 92% lower (P<0.001) in stenotic valves, whereas no significant changes in the expression of ANP and BNP genes were found compared with valves obtained from patients with aortic regurgitation. CNP was localized by immunohistochemistry with specific CNP (32-53) antibody to valvular endothelial cells and myofibroblasts. Gene expression of furin, which proteolytically cleaves proCNP into active CNP, was 54% lower in aortic valve stenosis (P=0.04). Moreover, natriuretic peptide receptor-A and natriuretic peptide receptor-B mRNA levels were 78% and 76% lower, respectively, in stenotic valves. In contrast, gene expression of corin, a proANP- and proBNP-converting enzyme, and natriuretic peptide receptor-C did not differ between groups.

Conclusions— We show that natriuretic peptides, their processing enzymes, and their receptors are expressed in human aortic valves. Aortic valve stenosis is characterized by distinct downregulation of gene expression of CNP, its processing enzyme furin, and the target receptors natriuretic peptide receptor-B and natriuretic peptide receptor-A, which suggests that CNP acts as a paracrine regulator of the aortic valve calcification process.

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