USE OF ENDOTHELIN RECEPTOR TYPE B AGONISTS FOR THE TREATMENT OF AORTIC VALVE STENOSIS

Abstract

Aortic valve stenosis (AS), is the most frequent valvular heart disease in Europe and affects more than 1 in 4 people over 65 years old. AS progression from fibrotic thickening to valvular leaflets calcification leads to heart failure development and eventually to death within 2 to 5 years after symptoms occurrence. The inventors now show that endothelin receptor type B (ETB) activation with an agonist decreased the calcium content of VIC. Therefore, the present invention relates to the use of endothelin receptor type B (ETB) agonists for the treatment of aortic valve stenosis.

Claims

1. A method of treating Aortic Valve Stenosis (AS) in a patient in need thereof comprising administering to the patient a therapeutically effective amount of an endothelin receptor type B (ET.sub.B) agonist.

2. A method of reversing, preventing, or delaying calcification of an aortic valve in a patient in need thereof comprising administering to the patient a therapeutically effective amount of an endothelin receptor type B (ET.sub.B) agonist.

3. The method of claim 2 wherein the aortic valve is an implanted bioprosthetic valve.

4. The method of claim 3, wherein the method prevents degeneration of the implanted bioprosthetic valve.

5. The method of claim 3, wherein the method delays or prevents calcification of the implanted bioprosthetic valve after valve replacement either surgically or after transcatheter aortic valve implantation (TAVI).

6. The method of claim 1 wherein the patient suffers from a calcific aortic valve disease (CAVD).

7. The method according to claim 1 wherein the endothelin receptor type B agonist is chosen from sarafotoxin 6c, IRL-1620, Endothelin 3, BQ-3020 and Ala(1,3,11,15)-Endothelin-1.

8. The method according to claim 1 wherein the endothelin receptor type B agonist is IRL-1620.

9. A method of making a bioprosthetic valve, comprising preparing the biosynthetic valve and entrapping a therapeutically effective amount of an endothelin receptor type B agonist into cusps of the valve.

10. A bioprosthetic valve comprising a therapeutically effective amount of an endothelin receptor type B agonist.

11. The bioprosthetic valve of claim 10 wherein the endothelin receptor type B agonist is entrapped into cusps of the valve.

12. A method of preventing or treating aortic valve stenosis in a patient in need thereof, comprising implanting the bioprosthetic valve of claim 10 into the patient.

13. The method according to claim 2, wherein the patient suffers from a calcific aortic valve disease (CAVD).

14. The method according to claim 2, wherein the endothelin receptor type B agonist is chosen from sarafotoxin 6c, IRL-1620, Endothelin 3, BQ-3020 and Ala(1,3,11,15)-Endothelin-1.

15. The method according to claim 2, wherein the endothelin receptor type B agonist is IRL-1620.

Description

FIGURES

[0055] FIG. 1: Calcium content of valvular interstitial cells (VIC) cultured in procalcifying conditions containing inorganic phosphate (Pi) in absence and in presence of antagonists of either the ET.sub.A or ET.sub.B receptors and a agonist of the ET.sub.B receptor. ET.sub.B receptor antagonist increases the calcium content of VIC while the ET.sub.B receptor agonist IRL 1620 decreases their calcium content compared to non-treated VIC.

EXAMPLE

Introduction

[0056] Calcified aortic stenosis (AS) is the most common acquired valvulopathy for which there is still no pharmacological treatment. Endothelin-1 (ET-1) is not only a powerful vasoconstrictor but also a pro-inflammatory and pro-fibrotic peptide whose role in AS remains unclear.

Objective

[0057] The aim of this study was to characterize the role of ET-1 in the aortic valve calcification.

Methods

[0058] Valvular endothelial cells (VEC), isolated from human aortic valves, were cultured in a cell perfusion system to assess ET-1 production in different fluid flow shear stress conditions. In addition, valvular interstitial cells (VIC) were cultured in a pro-calcifying culture medium containing inorganic phosphate (Pi) with or without antagonists of either the ET.sub.A or ETB receptor antagonists or with the agonist of the ET.sub.B receptor IRL 1620 during 10 days. Aortic valves from rats were also cultured in ex vivo and stimulated with ET-1 antagonists. Calcium content was assessed using an o-cresolphtalein-based assay and fluorescence by Osteosens. VEC prepro-ET-1 and VIC osteogenic mRNA expression levels were evaluated by RTqPCR.

Results

[0059] Turbulent shear stress, mimicking the flow conditions suffered by the valve at the aortic side increased VEC prepro-ET-1 mRNA expression level and ET-1 release compared to laminar shear stress. Calcium content and fluorescence by Osteosens staining of VIC and aortic valves were increased after blockade of ET.sub.B receptor and this effect was potentiated by concomitant blockade of ET.sub.A receptor. In contrast, the ET.sub.B receptor agonist IRL-1620 decreased the calcium content of VIC (FIG. 1). The mRNA expression of osteopontin, RUNX2, and BMP2 was similarly increased by ET.sub.A and ET.sub.B blockade.

Conclusion

[0060] These results support a protective role of the endothelin system against the development of AS. Further studies are warranted to characterize the intracellular pathways and to confirm these results in in vivo models.

REFERENCES

[0061] Throughout this application, various references describe the state of the art to which this invention pertains. The disclosures of these references are hereby incorporated by reference into the present disclosure.