真核翻译起始因子3a在右室重构中的作用及吴茱萸次碱治疗机制研究

Myocardial remodeling is an critical pathphysiological characteristic in heart failure development, while abnormal proliferation of myocardial fibroblast play an important role in the process of remodeling. However, the underlying mechanism of myocardial fibroblast proliferation induced by various pathogenic factors has not been well understood. Recent research reveals that eIF3a participates in tumor cell proliferation regulation. Previous experiments of the present project have found that TGF-β 1 promotes cell proliferation and raises eIF3a expression meanwhile in myocardial fibroblasts. In hypoxia induced pulmonary hypertension animal model, fluofenidone(capable of eIF3a inhibition), a new synthetic compound, is able to inhibit right ventricular remodeling significantly, CGRP can down regulate eIF3a expression and inhibit myofibroblast proliferation.. The present project is aim to confirm the crucial effect of eIF3a in myocardial remodeling using pulmonary hypertension animal model accompany with right ventricular remodeling induced by hypoxia and monocrotaline. We are also plan to reveal the mechanism of eIF3a expression induced by several immflamation factors such as TGF-β1 and the mechanism of cell proliferation induced by eIf3a. Furthermore, the functional and regulatory mechanism on inhibition of right ventricular remodeling by rutaecarpine will be well investigated. This project will be helpful to elucidate the pathogenesis of myocardial remodeling, and provide new insights for looking for prevention and treatment of heart failure.

心肌重构是心力衰竭发生发展的重要病理生理机制，而心肌成纤维细胞的异常增殖在心机重构中起重要作用。然而，不同致病因子诱导心肌成纤维细胞增殖的机制尚未完全明了。新近发现，eIF3a(翻译起始因子)参与肿瘤细胞增殖的调控。本项目预实验证明，在培养心肌纤维细胞，TGF-β1促进细胞增殖的同时上调eIF3a表达；在低氧诱发的肺动脉高压模型，新合成的化合物氟非尼酮（具有抑制eIF3a活性）能显著抑制血管重构与右室重构，降钙素基因相关肽下调eIF3a表达的同时抑制成纤维细胞增殖。本项目拟在低氧与野百合碱诱发肺动脉高压右室重构模型，确证eIF3a在心肌重构中的重要作用；在培养心肌纤维细胞，探讨某些炎性因子（如TGF-β1）上调eIF3a表达的机制及eIF3a促细胞增殖的机制。在此基础上，研究吴茱萸次碱抑制右室重构的作用及机制。本项目将有助于阐明心肌重构的发病机制，并为寻找防治心力衰竭的药物提供新思路。

心肌重构是心力衰竭发生发展的重要病理生理机制，而心肌成纤维细胞的异常增殖在心机重构中起重要作用。然而，不同致病因子诱导心肌成纤维细胞增殖的机制尚未完全明了。新近发现，eIF3a(翻译起始因子)参与肿瘤细胞增殖的调控。本项目在野百合碱与低氧诱发大鼠右心室重构模型，确证 eIF3a 在心肌重构中发挥重要作用；在培养的心肌成纤维细胞，研究 eIF3a 调控细胞增殖及机制；在动物或培养心肌成纤维细胞，研究吴茱萸次碱抑制心肌重构和 CGRP 抑制成纤维细胞增殖及机制。本项目将助于揭示心肌重构时成纤维细胞增殖的调控机制，并为寻找抗心肌重构药物提供新思路。

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