miR-375-IGF-1R-PI3K/Akt通路在血管生成中的作用及刺芒柄花素干预效果

Although estrogen has become a hotspot of cardiovascular disease therapy researches, it is also found closely associated with the development of cancers. Our previous studies have revealed that the phytoestrogen formononetin, structurally similar to estrogen, exhibited estrogenic activity in promoting endothelial cell proliferation, but without obvious effects on cancer cells. The results indicates formononetin may have potential cardiovascular protective effects by targeting endothelial cell functions. Based on our preceding discovery that formononetin regulated cell proliferation and apoptosis by affecting miR375 and IGF-1R-PI3K/Akt, we will utilize molecular techniques, cell biological techniques and ovariectomized mice model to identify that upregulated miR-375 are able to interfere with IGF-1R and PI3K/Akt pathway in vitro and in vivo. Accordingly, further research should be carried out to elucidate the relationship among formononetin, miR375-IGF-1R-PI3K/Akt signaling and downstream angiogenesis-related genes, which may promotes survival, migration and angiogenesis of endothelial cells. We anticipate that our findings will provide new insights into phytoestrogens' future clinical applications for prevention and treatment of cardiovascular disease.

雌激素心血管系统保护效应一直为研究热点，但其与肿瘤的发生也有密切关系。我们的前期研究证实植物雌激素刺芒柄花素因其结构类似于内源性雌激素，在体外表现出促内皮细胞增殖、抑制凋亡的拟雌激素效应，而对肿瘤细胞生长无明显作用，提示刺芒柄花素以内皮细胞为靶标，发挥心血管保护作用的可能。本研究在前期发现刺芒柄花素通过调节miR-375或IGF-1R-PI3K/Akt信号途径影响细胞增殖或凋亡的基础上，运用细胞生物学、分子生物学、动物模型等技术，探索miR-375、IGF-1R、PI3K/Akt在体内外的信号级联，重点论证刺芒柄花素通过对上述通路及下游血管生成相关基因的影响，促进内皮细胞增殖、迁移和血管生成，为植物雌激素预防和治疗心血管疾病提供新思路。

雌激素心血管系统保护效应一直为研究热点，但其与乳腺癌的发生也有密切关系，限制了其临床应用。我们的前期研究证实红三叶草的主要活性成分—刺芒柄花素是一种典型的植物雌激素，因其结构类似于内源性雌激素，在体外表现出促内皮细胞增殖、抑制凋亡的拟雌激素效应，而对乳腺癌细胞生长无明显作用，提示刺芒柄花素以内皮细胞为靶标，发挥心血管保护作用的可能。本研究在前期发现刺芒柄花素通过调节miR-375或IGF-1RPI3K/Akt信号途径影响内皮细胞增殖或凋亡的基础上，运用药物化学、生物信息学、细胞生物学、分子生物学、动物模型等技术，探索EWSAT1、TRAF6 、miR-375、IGF-1R、PI3K/Akt及c-jun在体内外的信号级联，重点论证刺芒柄花素及其改构物通过对上述通路及下游血管生成相关基因的影响，在体内外干预内皮细胞增殖、迁移和血管生成，为植物雌激素预防和治疗心血管疾病提供新思路，也为广西特色植物的开发提供新的平台。