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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Distinct roles of E2F proteins in vascular smooth muscle cell proliferation and intimal hyperplasia
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Distinct roles of E2F proteins in vascular smooth muscle cell proliferation and intimal hyperplasia

机译:E2F蛋白在血管平滑肌细胞增殖和内膜增生中的不同作用

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摘要

Intimal hyperplasia (IH) and restenosis limit the long-term utility of bypass surgery and angioplasty due to pathological proliferation and migration of vascular smooth muscle cells (VSMCs) into the intima of treated vessels. Consequently, much attention has been focused on developing inhibitory agents that reduce this pathogenic process. The E2F transcription factors are key cell cycle regulators that play important roles in modulating cell proliferation and cell fate. Nonselective E2F inhibitors have thus been extensively evaluated for this purpose. Surprisingly, these E2F inhibitors have failed to reduce IH. These findings prompted us to evaluate the roles of different E2Fs during IH to determine how selective targeting of E2F isoforms impacts VSMC proliferation. Importantly, we show that E2F3 promotes proliferation of VSMCs leading to increased IH, whereas E2F4 inhibits this pathological response. Furthermore, we use RNA probes to show that selective inhibition of E2F3, not global inhibition of E2F activity, significantly reduces VSMC proliferation and limits IH in murine bypass grafts.
机译:内膜增生(IH)和再狭窄由于病理性增生和血管平滑肌细胞(VSMC)进入治疗血管内膜的迁移而限制了旁路手术和血管成形术的长期应用。因此,许多注意力集中在开发减少这种致病过程的抑制剂上。 E2F转录因子是关键的细胞周期调节因子,在调节细胞增殖和细胞命运中起重要作用。因此已经为此目的广泛评估了非选择性E2F抑制剂。令人惊讶的是,这些E2F抑制剂未能降低IH。这些发现促使我们评估IH期间不同E2F的作用,以确定E2F同工型的选择性靶向如何影响VSMC增殖。重要的是,我们表明E2F3促进VSMC增殖,导致IH增加,而E2F4抑制这种病理反应。此外,我们使用RNA探针显示选择性抑制E2F3,而不是全局抑制E2F活性,可显着降低VSMC增殖并限制鼠旁路移植物中的IH。

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