高同型半胱氨酸血症诱导组织蛋白酶 V 介导的血管内皮炎症。
l-Homocysteine-induced cathepsin V mediates the vascular endothelial inflammation in hyperhomocysteinaemia.
机构信息
Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, China.
Center for Vascular Disease and Translational Medicine, The Third Xiangya Hospital of Central South University, Changsha, China.
出版信息
Br J Pharmacol. 2018 Apr;175(8):1157-1172. doi: 10.1111/bph.13920. Epub 2017 Aug 11.
BACKGROUND AND PURPOSE
Vascular inflammation, including the expression of inflammatory cytokines in endothelial cells, plays a critical role in hyperhomocysteinaemia-associated vascular diseases. Cathepsin V, specifically expressed in humans, is involved in vascular diseases through its elastolytic and collagenolytic activities. The aim of this study was to determine the effects of cathepsin V on l-homocysteine-induced vascular inflammation.
EXPERIMENTAL APPROACH
A high methionine diet-induced hyperhomocysteinaemic mouse model was used to assess cathepsin V expression and vascular inflammation. Cultures of HUVECs were challenged with l-homocysteine and the cathepsin L/V inhibitor SID to assess the pro-inflammatory effects of cathepsin V. Transfection and antisense techniques were utilized to investigate the effects of cathepsin V on the dual-specificity protein phosphatases (DUSPs) and MAPK pathways.
KEY RESULTS
Cathepsin L (human cathepsin V homologous) was increased in the thoracic aorta endothelial cells of hyperhomocysteinaemic mice; l-homocysteine promoted cathepsin V expression in HUVECs. SID suppressed the activity of cathepsin V and reversed the up-regulation of inflammatory cytokines (IL-6, IL-8 and TNF-α), adhesion and chemotaxis of leukocytes and vascular inflammation induced by l-homocysteine in vivo and in vitro. Increased cathepsin V promoted the degradation of DUSP6 and DUSP7, phosphorylation and subsequent nuclear translocation of ERK1/2, phosphorylation of STAT1 and expression of IL-6, IL-8 and TNF-α.
CONCLUSIONS AND IMPLICATIONS
This study has identified a novel mechanism, which shows that l-homocysteine-induced upregulation of cathepsin V mediates vascular endothelial inflammation under high homocysteine condition partly via ERK /STAT1 pathway. This mechanism could represent a potential therapeutic target in hyperaemia-associated vascular diseases.
LINKED ARTICLES
This article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc.
背景与目的
血管炎症，包括内皮细胞中炎性细胞因子的表达，在高同型半胱氨酸血症相关血管疾病中起着关键作用。组织蛋白酶 V 特异性在人类中表达，通过其弹性蛋白酶和胶原酶活性参与血管疾病。本研究的目的是确定组织蛋白酶 V 对 l-同型半胱氨酸诱导的血管炎症的影响。
实验方法
采用高蛋氨酸饮食诱导的高同型半胱氨酸血症小鼠模型来评估组织蛋白酶 V 的表达和血管炎症。用 l-同型半胱氨酸和组织蛋白酶 L/V 抑制剂 SID 刺激 HUVECs 培养物，以评估组织蛋白酶 V 的促炎作用。转染和反义技术用于研究组织蛋白酶 V 对双特异性蛋白磷酸酶（DUSPs）和 MAPK 途径的影响。
主要结果
高同型半胱氨酸血症小鼠胸主动脉内皮细胞中组织蛋白酶 L（人组织蛋白酶 V 同源物）增加；l-同型半胱氨酸促进 HUVECs 中组织蛋白酶 V 的表达。SID 抑制组织蛋白酶 V 的活性，并逆转 l-同型半胱氨酸在体内和体外诱导的炎性细胞因子（IL-6、IL-8 和 TNF-α）、白细胞黏附和趋化以及血管炎症的上调。增加的组织蛋白酶 V 促进 DUSP6 和 DUSP7 的降解、ERK1/2 的磷酸化和随后的核转位、STAT1 的磷酸化以及 IL-6、IL-8 和 TNF-α的表达。
结论和意义
本研究确定了一种新的机制，表明 l-同型半胱氨酸诱导的组织蛋白酶 V 上调介导高同型半胱氨酸条件下的血管内皮炎症，部分通过 ERK/STAT1 途径。该机制可能代表与高血症相关血管疾病的潜在治疗靶点。
相关文章
本文是心血管疾病中小分子聚焦专题的一部分。要查看该部分中的其他文章，请访问 http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc.
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