Vol.:(0123456789) 1 3 Basic Research in Cardiology (2018) 113:30 https://doi.org/10.1007/s00395-018-0689-7 ORIGINAL CONTRIBUTION Apolipoprotein A‑I proteolysis in aortic valve stenosis: role of cathepsin S C. Gebhard 1  · F. Maaf 1  · B. E. Stähli 1  · J. Dang 1  · W. Nachar 1  · A. B. de Oliveira Moraes 1  · A. E. Kernaleguen 1  · V. Lavoie 1  · M. Mecteau 1  · T. Mihalache‑Avram 1  · Y. Shi 1  · M. Chabot‑Blanchet 3  · D. Busseuil 1  · D. Rhainds 1,2  · E. Rhéaume 1,2  · Jean‑Claude Tardif 1,2 Received: 16 February 2018 / Revised: 26 May 2018 / Accepted: 12 June 2018 © Springer-Verlag GmbH Germany, part of Springer Nature 2018 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 efcacy of such therapy. An activatable probe using a quenched fuorescently 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 signifcantly 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 identifed metalloproteinases (MMP) as exerting the most potent proteolytic efect 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 degrada- tion in human plasma (p < 0.05 vs control) with the maximum efect seen in women (68.8%, p < 0.05 vs men). Accordingly, cathepsin S activity correlated signifcantly 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 signifcant independent predictor of disease severity in women (standardized beta coefcient 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. Keywords Protease activity · Apolipoprotein A-I · Aortic valve stenosis · Cathepsin S Introduction Aortic valve stenosis (AVS) is the most common valvu- lar heart disease in the Western world and its prevalence increases with age [32]. Currently, surgical or percutane- ous valve replacement remains the primary management for symptomatic AVS [32]. The pathophysiology of AVS appears to share many similarities with atherosclerosis [12]. Indeed, the development of AVS involves a combination of lipoprotein deposition, infammatory activation, increased oxidative stress, extracellular matrix remodeling and neo- vascularization, as well osteoblastic transdiferentiation of valvular myofbroblasts and subsequent valvular calcifca- tion [31]. The latter is a highly regulated molecular pro- cess characterized by the expression of osteogenic proteins and proteolytic enzymes such as matrix metalloproteinases (MMPs) and cathepsins that are secreted by activated mac- rophages and myofbroblast-like cells [1, 3, 36]. C. Gebhard and F. Maaf contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00395-018-0689-7) contains supplementary material, which is available to authorized users. * Jean-Claude Tardif jean-claude.tardif@icm-mhi.org 1 Montreal Heart Institute, Université de Montréal, 5000 Belanger Street, Montreal H1T 1C8, Canada 2 Department of Medicine, Université de Montréal, Montreal, Canada 3 Montreal Health Innovations Coordinating Centre (MHICC), Montreal, Canada