학술논문
Aortic valve calcification is promoted by interleukin-8 and restricted through antagonizing CXC motif chemokine receptor 2.
Document Type
Academic Journal
Author
Dhayni K; MP3CV Laboratory, UPJV UR 7517, University of Picardie Jules Verne, Avenue Laennec, 80054 Amiens, France.; Chabry Y; MP3CV Laboratory, UPJV UR 7517, University of Picardie Jules Verne, Avenue Laennec, 80054 Amiens, France.; Department of Cardiac Surgery, CHU Amiens-Picardie, 1 Rd-Point du Pr. Christian Cabrol, 80054 Amiens, France.; Hénaut L; MP3CV Laboratory, UPJV UR 7517, University of Picardie Jules Verne, Avenue Laennec, 80054 Amiens, France.; Avondo C; MP3CV Laboratory, UPJV UR 7517, University of Picardie Jules Verne, Avenue Laennec, 80054 Amiens, France.; Boudot C; MP3CV Laboratory, UPJV UR 7517, University of Picardie Jules Verne, Avenue Laennec, 80054 Amiens, France.; Ouled-Haddou H; HEMATIM Laboratory, UPJV UR 4666, Université de Picardie Jules Verne, Avenue Laennec, 80054 Amiens, France.; Bigot-Corbel E; Department of Clinical Biochemistry, CHU de Nantes, Bd Jacques-Monod, 44093 Saint-Herblain, France.; Touati G; Department of Cardiac Surgery, CHU Amiens-Picardie, 1 Rd-Point du Pr. Christian Cabrol, 80054 Amiens, France.; Caus T; MP3CV Laboratory, UPJV UR 7517, University of Picardie Jules Verne, Avenue Laennec, 80054 Amiens, France.; Department of Cardiac Surgery, CHU Amiens-Picardie, 1 Rd-Point du Pr. Christian Cabrol, 80054 Amiens, France.; Messaoudi H; EnVI Laboratory, INSERM UMR 1096, Rouen Normandy University, 22 Boulevard Gambetta, 76183 Rouen, France.; Bellien J; EnVI Laboratory, INSERM UMR 1096, Rouen Normandy University, 22 Boulevard Gambetta, 76183 Rouen, France.; Tribouilloy C; MP3CV Laboratory, UPJV UR 7517, University of Picardie Jules Verne, Avenue Laennec, 80054 Amiens, France.; Department of Cardiology, CHU Amiens-Picardie, 1 Rd-Point du Pr. Christian Cabrol, 80054 Amiens, France.; Messika-Zeitoun D; Department of Cardiology, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, Ontario, Canada.; Zibara K; Department of Biology, Faculty of Sciences, Lebanese University, Beirut, Lebanon.; Kamel S; MP3CV Laboratory, UPJV UR 7517, University of Picardie Jules Verne, Avenue Laennec, 80054 Amiens, France.; Bennis Y; MP3CV Laboratory, UPJV UR 7517, University of Picardie Jules Verne, Avenue Laennec, 80054 Amiens, France.; Department of Pharmacology, CHU Amiens-Picardie, 1 Rd-Point du Professeur Christian Cabrol, 80054 Amiens, France.
Source
Publisher: Oxford Journals Country of Publication: England NLM ID: 0077427 Publication Model: Print Cited Medium: Internet ISSN: 1755-3245 (Electronic) Linking ISSN: 00086363 NLM ISO Abbreviation: Cardiovasc Res Subsets: MEDLINE
Subject
Language
English
Abstract
Aims: Inflammatory cytokines play a critical role in the progression of calcific aortic valve disease (CAVD), for which there is currently no pharmacological treatment. The aim of this study was to test the hypothesis that interleukin-8 (IL-8), known to be involved in arterial calcification, also promotes aortic valve calcification (AVC) and to evaluate whether pharmacologically blocking the IL-8 receptor, CXC motif chemokine receptor 2 (CXCR2), could be effective in preventing AVC progression.
Methods and Results: A cohort of 195 patients (median age 73, 74% men) diagnosed with aortic valve stenosis (severe in 16.9% of cases) were prospectively followed by CT for a median time of 2.6 years. A Cox proportional hazards regression analysis indicated that baseline IL-8 serum concentrations were associated with rapid progression of AVC, defined as an annualized change in the calcification score by CT ≥ 110 AU/year, after adjustment for age, gender, bicuspid anatomy, and baseline disease severity. In vitro, exposure of primary human aortic valvular interstitial cells (hVICs) to 15 pg/mL IL-8 induced a two-fold increase in inorganic phosphate (Pi)-induced calcification. IL-8 promoted NFκB pathway activation, MMP-12 expression, and elastin degradation in hVICs exposed to Pi. These effects were prevented by SCH527123, an antagonist of CXCR2. The expression of CXCR2 was confirmed in hVICs and samples of aortic valves isolated from patients with CAVD, in which the receptor was mainly found in calcified areas, along with MMP-12 and a degraded form of elastin. Finally, in a rat model of chronic kidney disease-associated CAVD, SCH527123 treatment (1 mg/kg/day given orally for 11 weeks) limited the decrease in aortic cusp separation, the increase in maximal velocity of the transaortic jet, and the increase in aortic mean pressure gradient measured by echocardiography, effects that were associated with a reduction in hydroxyapatite deposition and MMP-12 expression in the aortic valves.
Conclusion: Overall, these results highlight, for the first time, a significant role for IL-8 in the progression of CAVD by promoting calcification via a CXCR2- and MMP-12-dependent mechanism that leads to elastin degradation, and identify CXCR2 as a promising therapeutic target for the treatment of CAVD.
Competing Interests: Conflict of interest: None declared.
(© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
Methods and Results: A cohort of 195 patients (median age 73, 74% men) diagnosed with aortic valve stenosis (severe in 16.9% of cases) were prospectively followed by CT for a median time of 2.6 years. A Cox proportional hazards regression analysis indicated that baseline IL-8 serum concentrations were associated with rapid progression of AVC, defined as an annualized change in the calcification score by CT ≥ 110 AU/year, after adjustment for age, gender, bicuspid anatomy, and baseline disease severity. In vitro, exposure of primary human aortic valvular interstitial cells (hVICs) to 15 pg/mL IL-8 induced a two-fold increase in inorganic phosphate (Pi)-induced calcification. IL-8 promoted NFκB pathway activation, MMP-12 expression, and elastin degradation in hVICs exposed to Pi. These effects were prevented by SCH527123, an antagonist of CXCR2. The expression of CXCR2 was confirmed in hVICs and samples of aortic valves isolated from patients with CAVD, in which the receptor was mainly found in calcified areas, along with MMP-12 and a degraded form of elastin. Finally, in a rat model of chronic kidney disease-associated CAVD, SCH527123 treatment (1 mg/kg/day given orally for 11 weeks) limited the decrease in aortic cusp separation, the increase in maximal velocity of the transaortic jet, and the increase in aortic mean pressure gradient measured by echocardiography, effects that were associated with a reduction in hydroxyapatite deposition and MMP-12 expression in the aortic valves.
Conclusion: Overall, these results highlight, for the first time, a significant role for IL-8 in the progression of CAVD by promoting calcification via a CXCR2- and MMP-12-dependent mechanism that leads to elastin degradation, and identify CXCR2 as a promising therapeutic target for the treatment of CAVD.
Competing Interests: Conflict of interest: None declared.
(© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)