缺氧对 CDK5RAP3 的抑制会激活 P38MAPK,从而促进血管生成。

IF 1.2 4区 医学 Q3 CARDIAC & CARDIOVASCULAR SYSTEMS
Mengmeng Zhang, Liu Yang, Jun Shu, Xin Gu, Yan Han
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引用次数: 0

摘要

CDK5RAP3 是一种公认的肿瘤抑制因子,可抑制 Chk1 和 Chk2 并激活 p53,所有这些因子都参与介导毒素诱导的癌细胞凋亡。CDK5RAP3 还通过介导 p38 与野生型 p53 诱导的磷酸酶 1 的相互作用来抑制 p38MAPK 的磷酸化和活性。本研究旨在探讨 CDK5RAP3 在缺氧条件下对人脐静脉内皮细胞(HUVECs)的抗血管生成活性及其分子机制。血管内皮生长因子(VEGF)是诱导 HUVECs 血管生成的主要因素。在 2%O2 的缺氧处理条件下,HUVECs 的 CDK5RAP3 水平呈时间依赖性降低。CDK5RAP3 的减少伴随着 p38MAPK 磷酸化和活化的增加。研究发现,中度缺氧可显著增加分泌的血管内皮生长因子浓度,缺氧条件培养基(HCM)可明显增强增殖、迁移和管形成。我们的研究结果表明,中度缺氧通过抑制 CDK5RAP3 促进血管生成。CDK5RAP3 在血管再生中具有明显的调节作用,因为下调其在内皮细胞中的表达可促进血管内皮生长因子的合成,进而改善细胞迁移和管腔形成能力。本研究提出的证据表明,适度缺氧可通过抑制 CDK5RAP3 促进血管生成,这表明 CKD5RAP3 有可能成为一种有效的抗血管生成药物,用于调节癌症、缺血性疾病和伤口愈合的血管生成。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
CDK5RAP3 Inhibition by Hypoxia Activates P38MAPK to Facilitate Angiogenesis.

CDK5RAP3 is a recognized tumor suppressor that inhibits Chk1 and Chk2 and activates p53, all of which are involved with mediating toxin-induced apoptosis of cancer cells. CDK5RAP3 also inhibits p38MAPK phosphorylation and activity via mediating a p38 interaction with wild-type p53-induced phosphatase 1. This study aimed to investigate the antiangiogenic activity of CDK5RAP3 and its molecular mechanisms in human umbilical vein endothelial cells (HUVECs) under conditions of hypoxic conditions. Angiogenesis was induced in HUVECs mainly by vascular endothelial growth factor (VEGF). The CDK5RAP3 levels of HUVECs were reduced in a time-dependent manner in response to hypoxic treatment at 2% O2. The reduction of CDK5RAP3 was accompanied with increased p38MAPK phosphorylation and activation. Moderate hypoxia was found to significantly increase secreted VEGF concentrations, and the hypoxic conditioned medium (HCM) markedly enhanced proliferation, migration, and tube formation. Our findings indicate that moderate hypoxia facilitates angiogenesis by inhibiting CDK5RAP3. CDK5RAP3 exhibits a clear regulatory role in vascular regeneration, as downregulating its expression in endothelial cells enhances VEGF synthesis and subsequently improves cell migration and lumen formation capability. This study presents evidence indicating that moderate hypoxia facilitates angiogenesis by inhibiting CDK5RAP3, demonstrating the potential for CKD5RAP3 to be a potent antiangiogenic agent in angiogenesis regulation of cancer, ischemic diseases, and wound healing.

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来源期刊
International heart journal
International heart journal 医学-心血管系统
CiteScore
2.50
自引率
6.70%
发文量
148
审稿时长
6-12 weeks
期刊介绍: Authors of research articles should disclose at the time of submission any financial arrangement they may have with a company whose product figures prominently in the submitted manuscript or with a company making a competing product. Such information will be held in confidence while the paper is under review and will not influence the editorial decision, but if the article is accepted for publication, the editors will usually discuss with the authors the manner in which such information is to be communicated to the reader.
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