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凝血酶通过钙介导的肠肌成纤维细胞胞质磷脂酶A激活诱导细胞凋亡。

Thrombin Induced Apoptosis through Calcium-Mediated Activation of Cytosolic Phospholipase A in Intestinal Myofibroblasts.

作者信息

Park Mi Ja, Won Jong Hoon, Kim Dae Kyong

机构信息

Department of Environmental & Health Chemistry, College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea.

出版信息

Biomol Ther (Seoul). 2023 Jan 1;31(1):59-67. doi: 10.4062/biomolther.2022.043. Epub 2022 Sep 2.

DOI:10.4062/biomolther.2022.043
PMID:36052603
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9810453/
Abstract

Thrombin is a serine protease that participates in a variety of biological signaling through protease-activated receptors. Intestinal myofibroblasts play central roles in maintaining intestinal homeostasis. In this study, we found that thrombin-induced apoptosis is mediated by the calcium-mediated activation of cytosolic phospholipase A in the CCD-18Co cell. Thrombin reduced cell viability by inducing apoptosis and proteinase-activated receptor-1 antagonist attenuated thrombin-induced cell death. Endogenous ceramide did not affect the cell viability itself, but a ceramide-mediated pathway was involved in thrombin-induced cell death. Thrombin increased intracellular calcium levels and cytosolic phospholipase A activity. The ceramide synthase inhibitor Fumonisin B, intracellular calcium chelator BAPTA-AM, and cytosolic phospholipase A inhibitor AACOCF inhibited thrombin-induced cell death. Thrombin stimulated arachidonic acid release and reactive oxygen species generation, which was blocked by AACOCF, BAPTA-AM, and the antioxidant reagent Trolox. Taken together, thrombin triggered apoptosis through calcium-mediated activation of cytosolic phospholipase A in intestinal myofibroblasts.

摘要

凝血酶是一种丝氨酸蛋白酶，通过蛋白酶激活受体参与多种生物信号传导。肠道肌成纤维细胞在维持肠道内环境稳定中起核心作用。在本研究中，我们发现凝血酶诱导的细胞凋亡是由CCD - 18Co细胞中钙介导的胞质磷脂酶A激活所介导的。凝血酶通过诱导细胞凋亡降低细胞活力，蛋白酶激活受体-1拮抗剂可减轻凝血酶诱导的细胞死亡。内源性神经酰胺本身不影响细胞活力，但神经酰胺介导的途径参与了凝血酶诱导的细胞死亡。凝血酶增加细胞内钙水平和胞质磷脂酶A活性。神经酰胺合酶抑制剂伏马菌素B、细胞内钙螯合剂BAPTA - AM和胞质磷脂酶A抑制剂AACOCF均可抑制凝血酶诱导的细胞死亡。凝血酶刺激花生四烯酸释放和活性氧生成，这被AACOCF、BAPTA - AM和抗氧化剂Trolox所阻断。综上所述，凝血酶通过钙介导的肠道肌成纤维细胞胞质磷脂酶A激活引发细胞凋亡。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0fea/9810453/81e65951465b/bt-31-1-59-f6.jpg
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Inflamm Bowel Dis. 2021 Nov 15;27(Suppl 2):S33-S37. doi: 10.1093/ibd/izab244.
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Increased Mucosal Thrombin is Associated with Crohn's Disease and Causes Inflammatory Damage through Protease-activated Receptors Activation.黏膜组织凝血酶水平升高与克罗恩病相关，并通过蛋白酶激活受体的激活导致炎症损伤。
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Interaction of Synaptosomal-Associated Protein 25 with Neutral Sphingomyelinase 2: Functional Impact on the Sphingomyelin Pathway.
突触相关蛋白 25 与中性鞘磷脂酶 2 的相互作用：对鞘磷脂途径的功能影响。
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Active thrombin produced by the intestinal epithelium controls mucosal biofilms.肠上皮细胞产生的活性凝血酶控制黏膜生物膜。
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Functional Proteomic Profiling of Secreted Serine Proteases in Health and Inflammatory Bowel Disease.健康和炎症性肠病中分泌丝氨酸蛋白酶的功能蛋白质组学分析。
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ANGPTL2 expression in the intestinal stem cell niche controls epithelial regeneration and homeostasis.肠道干细胞微环境中的血管生成素样蛋白2（ANGPTL2）表达调控上皮再生与稳态。
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