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拉巴胺素,但不是FK-506,增加内皮组织因子表达:对药物释放支架设计的影响

Jan Steffel¹, Roberto A Latini, Alexander Akhmedov

¹Cardiovascular Research, Physiology Institute, Center for Integrative Human Physiology, University of Zurich, CH-8057 Zürich, Switzerland.

|September 21, 2005

概括

拉巴胺在人类大动脉内皮细胞中增加了组织因子 (TF) 表达,但不是光滑肌细胞. 这一发现与释放药物的支架设计和患者治疗有关.

科学领域:

血管生物学血管生物学
药理学药理学是指药理学的学科.
生物化学生物化学

背景情况:

药物排泄支架影响血管细胞生物学.
组织因子 (TF) 表达在血管反应中至关重要.
拉帕米辛和FK-506是用于支架的关键药物.

研究的目的:

研究拉巴胺素和FK-506对人类大动脉内皮细胞 (HAEC) 和血管光滑肌细胞 (HAVSMC) TF表达的影响.

主要方法:

细胞 (HAEC 和 HAVSMC) 用拉帕或 FK-506.6 进行治疗.
在用血栓激素或TNF-alpha刺激后测量了TF表达.
分析了蛋白质酸化 (p70S6K,p38,ERK,JNK) 和TF mRNA水平.

主要成果:

拉巴胺以剂量依赖的方式在HAEC中增强了血栓和TNF-α诱导的TF表达.
拉巴胺在HAEC中增加了40%的基底TF水平,但在HAVSMC中没有影响.
在任何一种细胞类型中,FK-506都没有增强TF表达;它也对抗了拉巴胺素的作用.
拉帕米辛抑制了p70S6K的酸化,并在转录后影响了TF的表达.

结论:

拉巴胺素与FK-506不同,通过哺乳动物目标拉巴胺素 (mTOR) 抑制,部分在转录后水平上调节HAEC中的TF表达.
这种效果取决于结合FK结合蛋白-12.
这些发现对药物释放支架设计和抗血栓治疗管理具有临床意义.

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