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Apolipoprotein A-I proteolysis in aortic valve stenosis: role of cathepsin S

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Abstract

Aortic valve stenosis (AVS) is the most common valvular heart disease in the Western world. Therapy based on apolipoprotein A-I (apoA-I), the major protein component of high-density lipoproteins, results in AVS regression in experimental models. Nevertheless, apoA-I degradation by proteases might lead to suboptimal efficacy of such therapy. An activatable probe using a quenched fluorescently labeled full-length apoA-I protein was generated to assess apoA-I-degrading protease activity in plasma derived from 44 men and 20 women with severe AVS (age 65.0 ± 10.4 years) as well as from a rabbit model of AVS. In human and rabbit AVS plasma, apoA-I-degrading protease activity was significantly higher than in controls (humans: 0.038 ± 0.009 vs 0.022 ± 0.005 RFU/s, p < 0.0001; rabbits: 0.033 ± 0.016 vs 0.017 ± 0.005 RFU/s, p = 0.041). Through the use of protease inhibitors, we identified metalloproteinases (MMP) as exerting the most potent proteolytic effect on apoA-I in AVS rabbits (67%, p < 0.05 vs control), while the cysteine protease cathepsin S accounted for 54.2% of apoA-I degradation in human plasma (p < 0.05 vs control) with the maximum effect seen in women (68.8%, p < 0.05 vs men). Accordingly, cathepsin S activity correlated significantly with mean transaortic pressure gradient in women (r = 0.5, p = 0.04) but not in men (r = − 0.09, p = 0.60), and was a significant independent predictor of disease severity in women (standardized beta coefficient 0.832, p < 0.001) when tested in a linear regression analysis. ApoA-I proteolysis is increased in AVS. Targeting circulating cathepsin S may lead to new therapies for human aortic valve disease.

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Funding

This work was supported by the Swiss National Science Foundation (SNSF, grants P3SMP3_151740/1142741 to BES and CG), the Novartis Foundation for Medical-Biological Research, Switzerland (to BES and CG), and the Gottfried und Julia Bangerter-Rhyner-Foundation, Switzerland (to BES). Dr. Tardif holds the Canada Research Chair in translational and personalized medicine and the Pfizer-endowed research chair in atherosclerosis at the Université de Montréal.

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  1. C. Gebhard and F. Maafi contributed equally to this work.

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  1. Montreal Heart Institute, Université de Montréal, 5000 Belanger Street, Montreal, H1T 1C8, Canada

    C. Gebhard, F. Maafi, B. E. Stähli, J. Dang, W. Nachar, A. B. de Oliveira Moraes, A. E. Kernaleguen, V. Lavoie, M. Mecteau, T. Mihalache-Avram, Y. Shi, D. Busseuil, D. Rhainds, E. Rhéaume & Jean-Claude Tardif

  2. Department of Medicine, Université de Montréal, Montreal, Canada

    D. Rhainds, E. Rhéaume & Jean-Claude Tardif

  3. Montreal Health Innovations Coordinating Centre (MHICC), Montreal, Canada

    M. Chabot-Blanchet

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Dr. Tardif has received research grants from Amarin, AstraZeneca, DalCor, Esperion, Ionis, Merck, Pfizer, Sanofi, and Servier; received honoraria from DalCor, Pfizer, Sanofi, and Servier; and holds minor equity interest in DalCor. The other authors report no conflict of interest. Dr Gebhard and Dr Stähli have received research grants from the Novartis Foundation, Switzerland.

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Gebhard, C., Maafi, F., Stähli, B.E. et al. Apolipoprotein A-I proteolysis in aortic valve stenosis: role of cathepsin S. Basic Res Cardiol 113, 30 (2018). https://doi.org/10.1007/s00395-018-0689-7

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