弹性蛋白酶在人类皮肤中的表达及其与年龄相关的弹性蛋白降解的关系。,Biochimica et Biophysica Acta (BBA) - General Subjects

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弹性蛋白酶在人类皮肤中的表达及其与年龄相关的弹性蛋白降解的关系。
Biochimica et Biophysica Acta (BBA) - General Subjects ( IF 2.8 ) Pub Date : 2020-01-30 , DOI: 10.1016/j.bbagen.2020.129544
Preety Panwar ₁ , Tobias Hedtke ₂ , Andrea Heinz ₃ , Pierre-Marie Andrault ₁ , Wolfgang Hoehenwarter ₄ , David J Granville ₅ , Christian E H Schmelzer ₂ , Dieter Brömme ₆

Affiliation

Department of Oral Biological and Medical Sciences, Faculty of Dentistry, University of British Columbia, Vancouver, BC V6T1Z3, Canada; Centre for Blood Research, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
Institute of Pharmacy, Faculty of Natural Sciences I, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany; Fraunhofer Institute for Microstructure of Materials and Systems IMWS, Halle (Saale), Germany.
Institute of Pharmacy, Faculty of Natural Sciences I, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany; Department of Pharmacy, University of Copenhagen, Copenhagen, Denmark.
Proteome Analytics Research Group, Leibniz Institute for Plant Biochemistry, Halle (Saale), Germany.
ICORD Centre and Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V5Z1M9, Canada.
Department of Oral Biological and Medical Sciences, Faculty of Dentistry, University of British Columbia, Vancouver, BC V6T1Z3, Canada; Centre for Blood Research, University of British Columbia, Vancouver, BC V6T 1Z3, Canada; Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada V6T1Z3.

背景技术皮肤老化与细胞外基质中的结构功能变化有关，这部分是由蛋白水解降解引起的。由于半胱氨酸组织蛋白酶是主要的降解基质蛋白的蛋白酶，因此我们研究了人类皮肤中弹性蛋白酶K，S和V的年龄依赖性表达，它们在体外对弹性纤维网络完整性，切割特异性和释放生物活性肽。方法使用免疫组织化学和生物化学测定，扫描电子显微镜和质谱法，从年轻到非常老的供体中评估组织蛋白酶介导的人类皮肤弹性蛋白样品的降解。结果分析了来自10至86岁患者的弹性蛋白样品，结果显示，随着年龄的增长，纤维结构从稀薄的原纤维的致密网络变成珠状且多孔的网状结构，随年龄而变劣。在具有主要表皮表达的老年皮肤中观察到组织蛋白酶K，S和V的水平降低。组织蛋白酶V是最有效的弹性蛋白酶，其次是组织蛋白酶K和S。降解的弹性蛋白纤维的生物力学分析证实了组织蛋白酶的破坏活性。弹性蛋白中裂解位点的质谱测定表明，所有三种组织蛋白酶主要在疏水域中裂解。弹性蛋白的降解有效地被植物性抑制剂所抑制。此外，弹性蛋白纤维的降解导致生物活性肽的释放，以前与各种病理相关。结论组织蛋白酶是强大的弹性蛋白降解酶，能够产生多种弹性蛋白。它们可能是减少皮肤老化的干预策略的可行目标。

"点击查看英文标题和摘要"

Expression of elastolytic cathepsins in human skin and their involvement in age-dependent elastin degradation.

BACKGROUND Skin ageing is associated with structure-functional changes in the extracellular matrix, which is in part caused by proteolytic degradation. Since cysteine cathepsins are major matrix protein-degrading proteases, we investigated the age-dependent expression of elastolytic cathepsins K, S, and V in human skin, their in vitro impact on the integrity of the elastic fibre network, their cleavage specificities, and the release of bioactive peptides. METHODS Cathepsin-mediated degradation of human skin elastin samples was assessed from young to very old human donors using immunohistochemical and biochemical assays, scanning electron microscopy, and mass spectrometry. RESULTS Elastin samples derived from patients between 10 and 86 years of age were analysed and showed an age-dependent deterioration of the fibre structure from a dense network of thinner fibrils into a beaded and porous mesh. Reduced levels of cathepsins K, S, and V were observed in aged skin with a predominant epidermal expression. Cathepsin V was the most potent elastase followed by cathepsin K and S. Biomechanical analysis of degraded elastin fibres corroborated the destructive activity of cathepsins. Mass spectrometric determination of the cleavage sites in elastin revealed that all three cathepsins predominantly cleaved in hydrophobic domains. The degradation of elastin was efficiently inhibited by an ectosteric inhibitor. Furthermore, the degradation of elastin fibres resulted in the release of bioactive peptides, which have previously been associated with various pathologies. CONCLUSION Cathepsins are powerful elastin-degrading enzymes and capable of generating a multitude of elastokines. They may represent a viable target for intervention strategies to reduce skin ageing.

更新日期：2020-01-31

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