Montreal Heart Institute, Université de Montréal, 5000 Belanger Street, Montreal, H1T 1C8, Canada.
Montreal Health Innovations Coordinating Centre (MHICC), Montreal, Canada.
Basic Res Cardiol. 2018 Jun 18;113(4):30. doi: 10.1007/s00395-018-0689-7.
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.
主动脉瓣狭窄（AVS）是西方世界最常见的瓣膜性心脏病。基于载脂蛋白 A-I（apoA-I）的治疗，apoA-I 是高密度脂蛋白的主要蛋白成分，可导致实验模型中的 AVS 消退。然而，蛋白酶对 apoA-I 的降解可能导致这种治疗的效果不理想。生成了一种使用淬灭荧光标记全长 apoA-I 蛋白的可激活探针，以评估源自 44 名男性和 20 名女性严重 AVS（年龄 65.0±10.4 岁）以及 AVS 兔模型的血浆中 apoA-I 降解蛋白酶的活性。在人类和兔 AVS 血浆中，apoA-I 降解蛋白酶的活性明显高于对照组（人类：0.038±0.009 与 0.022±0.005 RFU/s，p<0.0001；兔：0.033±0.016 与 0.017±0.005 RFU/s，p=0.041）。通过使用蛋白酶抑制剂，我们确定金属蛋白酶（MMP）对 AVS 兔的 apoA-I 具有最强的蛋白水解作用（67%，p<0.05 与对照相比），而半胱氨酸蛋白酶组织蛋白酶 S 则占人类血浆中 apoA-I 降解的 54.2%（p<0.05 与对照相比），最大作用见于女性（68.8%，p<0.05 与男性相比）。因此，组织蛋白酶 S 活性与女性平均主动脉瓣跨瓣压力梯度显著相关（r=0.5，p=0.04），但与男性无关（r=-0.09，p=0.60），并且在女性中是疾病严重程度的显著独立预测因子线性回归分析时（标准化β系数 0.832，p<0.001）。AVS 中 apoA-I 的蛋白水解增加。靶向循环组织蛋白酶 S 可能为人类主动脉瓣疾病提供新的治疗方法。
