背景:暴露于慢性心理压力是代谢性心血管疾病的危险因素。鉴于溶酶体CTSS(组织蛋白酶S)在人类病理生物学中的重要作用,我们检查了CTSS在应激相关血栓形成中的作用,专注于炎症,氧化应激,和凋亡。
方法:6周龄野生型小鼠(CTSS+/+)和CTSS缺陷小鼠(CTSS-/-)随机分配到非应激和2周固定应激组,接受氯化铁(FeCl3)诱导的颈动脉血栓形成手术进行形态学和生化研究。
结果:在压力/手术后第14天,应激增加了CTSS+/+小鼠的血栓长度和重量,加上PAI-1(血浆纤溶酶原激活抑制剂-1)水平的有害变化,ADAMTS13(一种具有血小板反应蛋白13型基序的解整合素连接和金属蛋白酶),和vWF(vonWillebrand因子)和动脉组织CTSS表达。与非应激CTSS+/+小鼠相比,应激CTSS-/-小鼠的PAI-1,vWF,TNF(肿瘤坏死因子)-α,白细胞介素-1β,toll样受体-4,裂解半胱天冬酶3,细胞色素c,p16INK4A,gp91phox,p22phox,ICAM-1(细胞间粘附分子-1),MCP-1(单核细胞趋化蛋白-1),MyD88(髓样分化原发反应88),和MMP(基质金属蛋白酶)-2/-9以及ADAMTS13,SOD(超氧化物歧化酶)-1/-2,eNOS(内皮NO合酶)的水平升高,p-Akt(蛋白激酶B),Bcl-2(B细胞淋巴瘤-2),p-GSK3α/β(糖原合成酶激酶α和β),和p-Erk1/2(细胞外信号调节激酶1和2)mRNA和/或蛋白质。CTSS缺失也减少了动脉血栓面积和内皮丢失。CTSS的药理抑制作用发挥了血管保护作用。体外,CTSS沉默和过表达,分别,降低和增加应激血清和氧化应激诱导的人脐静脉内皮细胞凋亡,它们改变了凋亡相关蛋白。
结论:CTSS抑制似乎改善了接受FeCl3诱导手术的小鼠的应激相关血栓形成,可能是通过减少血管炎症,氧化应激,和凋亡。因此,CTSS可能成为代谢性心血管疾病中慢性心理应激相关血栓事件的候选治疗靶点。
Exposure to chronic psychological stress is a risk factor for metabolic cardiovascular disease. Given the important role of lysosomal CTSS (
cathepsin S) in human pathobiology, we examined the role of CTSS in stress-related thrombosis, focusing on inflammation, oxidative stress, and apoptosis.
Six-week-old wild-type mice (CTSS+/+) and CTSS-deficient mice (CTSS-/-) randomly assigned to nonstress and 2-week immobilization stress groups underwent iron chloride3 (FeCl3)-induced carotid thrombosis surgery for morphological and biochemical studies.
On day 14 poststress/surgery, stress had increased the lengths and weights of thrombi in the CTSS+/+ mice, plus harmful changes in the levels of PAI-1 (plasminogen activation inhibitor-1), ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 13 motifs), and vWF (von Willebrand factor) and arterial tissue CTSS expression. Compared to the nonstressed CTSS+/+ mice, the stressed CTSS-/- mice had decreased levels of PAI-1, vWF, TNF (tumor necrosis factor)-α, interleukin-1β, toll-like receptor-4, cleaved-caspase 3, cytochrome c, p16INK4A, gp91phox, p22phox, ICAM-1 (intercellular adhesion molecule-1), MCP-1 (monocyte chemoattractant protein-1), MyD88 (myeloid differentiation primary response 88), and MMP (matrix metalloproteinase)-2/-9 and increased levels of ADAMTS13, SOD (superoxide dismutase)-1/-2, eNOS (endothelial NO synthase), p-Akt (phospho-protein kinase B), Bcl-2 (B-cell lymphoma-2), p-GSK3α/β (phospho-glycogen synthase kinases alpha and beta), and p-Erk1/2 (phospho-extracellular signal-regulated kinase 1 and 2) mRNAs and/or proteins. CTSS deletion also reduced the arterial thrombus area and endothelial loss. A pharmacological inhibition of CTSS exerted a vasculoprotective action. In vitro, CTSS silencing and overexpression, respectively, reduced and increased the stressed serum and oxidative stress-induced apoptosis of human umbilical vein endothelial cells, and they altered apoptosis-related proteins.
CTSS inhibition appeared to improve the stress-related thrombosis in mice that underwent FeCl3-induction surgery, possibly by reducing vascular inflammation, oxidative stress, and apoptosis. CTSS could thus become a candidate therapeutic target for chronic psychological stress-related thrombotic events in metabolic cardiovascular disease.