European Heart Journal Advance Access originally published online on May 15, 2007
European Heart Journal 2007 28(15):1894-1903; doi:10.1093/eurheartj/ehm129
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Increased expression of profibrotic neutral endopeptidase and bradykinin type 1 receptors in stenotic aortic valves
1 Wihuri Research Institute, Kalliolinnantie 4, Fin-00140 Helsinki, Finland
2 Minerva Institute for Medical Research, Helsinki, Finland
3 Division of Cardiology, Helsinki University Central Hospital, Helsinki, Finland
4 Division of Cardiothoracic Surgery, Helsinki University Central Hospital, Helsinki, Finland
Received 26 October 2006; revised 21 March 2007; accepted 29 March 2007; online publish-ahead-of-print 15 May 2007.
* Corresponding author. Tel: +358 9 681 411; fax: +358 9 637 476. E-mail address: petri.kovanen{at}wri.fi
See page 1795 for the editorial comment on this article (doi:10.1093/eurheartj/ehm259)
Aims: In aortic stenosis (AS), adverse remodelling of the valves may depend on altered local regulation of pro- and antifibrotic systems. We have recently shown that angiotensin-converting enzyme (ACE), which generates profibrotic angiotensin II and inactivates antifibrotic bradykinin (BK), is upregulated in stenotic aortic valves. Here, we analyse the expression of neutral endopeptidase (NEP), another profibrotic and BK-degrading enzyme, and of BK receptors in aortic valves in AS.
Methods and results: Stenotic aortic valves (n = 86) were obtained at valve replacement surgery and control valves (n = 13) at cardiac transplantation. Expression levels of NEP and BK type 1 and 2 receptors (BK-1R and BK-2R) in aortic valves and in isolated valvular myofibroblasts were analysed by real-time PCR and immunohistochemistry, and NEP activity was quantified by autoradiography. NEP, BK-1R, and BK-2R mRNA levels were higher in stenotic than in non-stenotic valves (P < 0.05 for each) and the respective proteins localized to valvular endothelial cells and myofibroblasts. In stenotic valves, the proteolytic activity of NEP was significantly increased (4.5-fold, P < 0.001), and tumour necrosis factor-
induced the expression of NEP in cultured myofibroblasts. Finally, treatment of cultured myofibroblasts with an NEP inhibitor (phosphoramidon) downregulated the expression of profibrotic transforming growth factor-ß1, whereas addition of BK decreased the expression of collagens I and III which was reversed by a BK-2R antagonist.
Conclusion: NEP activity is increased in stenotic aortic valves in parallel with increased expression of BK-receptors. The upregulation of NEP and BK-1R have the potential to promote valvular fibrosis and remodelling while the increase in BK-2R may represent a compensatory antifibrotic response. These findings add novel pathogenic insight and raise potential new therapeutic targets in AS.
Key Words: Aortic stenosis • Bradykinin • NEP • Valve
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