靶向 p27kip1 在斑块脆弱性中的治疗潜力

Archives of internal medicine research Pub Date : 2024-01-01 Epub Date: 2024-04-22 DOI:10.26502/aimr.0167
Jerry Trinh, Jennifer Shin, Vikrant Rai, Devendra K Agrawal
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引用次数: 0

摘要

动脉粥样硬化是冠状动脉疾病的重要诱因,它包括胆固醇、纤维蛋白和脂质在动脉壁内的积聚,引发炎症反应,最终形成斑块。这种多方面的相互作用包括过度纤维化、脂肪斑块形成、血管平滑肌细胞(VSMC)增殖以及白细胞迁移对炎症途径的反应。稳定的斑块能抵御并发症的侵袭,而脆弱的斑块则会导致血栓形成、心肌梗死、中风和急性脑血管意外。VSMC 的细微表型受基因调控和环境因素的影响,仍然至关重要。α-SMA、肌球蛋白重链和钙蛋白等重要标志物可调节 VSMC 的迁移和收缩,但在 VSMC 脱分化和增殖过程中表达会减少。IL-6家族细胞因子Oncostatin M(OSM)与MMP上调和泡沫细胞形成有关,影响斑块的发展。以抑制哺乳动物雷帕霉素靶标(mTOR)为目标的研究,特别是使用雷帕霉素及其类似物,显示出了潜力,但由于相关的不良反应,也带来了挑战。探索 p27kip 对斑块巨噬细胞的影响是一条大有可为的途径,但其全部治疗潜力仍有待开发。同样,虽然 OSM 在通过 p27kip 诱导细胞周期停滞方面表现出了潜力,但直接的联系还需要进一步研究。这篇重要综述讨论了 mTOR、p27kip 和 OSM 在血管内皮细胞增殖和分化中的作用,以及针对动脉粥样硬化中这些介质的治疗潜力,以减轻斑块的脆弱性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Therapeutic Potential of Targeting p27kip1 in Plaque Vulnerability.

Atherosclerosis, a critical contributor to coronary artery diseases, involves the accumulation of cholesterol, fibrin, and lipids within arterial walls, inciting inflammatory reactions culminating in plaque formation. This multifaceted interplay encompasses excessive fibrosis, fatty plaque development, vascular smooth muscle cell (VSMC) proliferation, and leukocyte migration in response to inflammatory pathways. While stable plaques demonstrate resilience against complications, vulnerable ones, with lipid-rich cores, necrosis, and thin fibrous caps, lead to thrombosis, myocardial infarction, stroke, and acute cerebrovascular accidents. The nuanced phenotypes of VSMCs, modulated by gene regulation and environmental cues, remain pivotal. Essential markers like alpha-SMA, myosin heavy chain, and calponin regulate VSMC migration and contraction, exhibiting diminished expression during VSMC de-differentiation and proliferation. p27kip, a CDK inhibitor, shows promise in regulating VSMC proliferation and appears associated with TNF-α-induced pathways impacting unstable plaques. Oncostatin M (OSM), an IL-6 family cytokine, correlates with MMP upregulation and foam cell formation, influencing plaque development. Efforts targeting mammalian target of rapamycin (mTOR) inhibition, notably using rapamycin and its analogs, demonstrate potential but pose challenges due to associated adverse effects. Exploration of the impact of p27kip impact on plaque macrophages presents promising avenues, yet its complete therapeutic potential remains untapped. Similarly, while OSM has exhibited potential in inducing cell cycle arrest via p27kip, direct links necessitate further investigation. This critical review discusses the role of mTOR, p27kip, and OSM in VSMC proliferation and differentiation followed by the therapeutic potential of targeting these mediators in atherosclerosis to attenuate plaque vulnerability.

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