外源性摄入对GGPP稳态及他汀药效的影响与机制

Statins, together with restricted uptake of exogenous cholesterol, is effective in slowing progression of cardiovascular diseases by inhibiting HMG-CoA reductase and the synthesis of endogenous cholesterol. Cell and animal experiments consistently showed the great promise of statins in treating pulmonary hypertension, the clinical trials however did not confirm their effectiveness. In addition to cholesterol, the efficiency of statins also depends on their inhibition on the synthesis of geranylgeranyl pyrophosphate (GGPP), another biologically potent end product of HMG-CoA reductase-controlled pathway. No any literature is available so far about the possible link between the efficiency of statins and GGPP. Since GGPP are abundant in our daily food, our pilot studies identified that the rat plasma GGPP level is greatly influenced by food-derived GGPP and is possibly the crucial reason for the controversial effect of statins. Accordingly, we design this project to observe the influence of daily food on plasma GGPP level, to evaluate the potential role of food-derived GGPP in the development of pulmonary hypertension and their restrictive effect on statins. We will also perform studies in animals to identify the protective role of the natural and specific antagonist of GGPP, which is rich in garlic extracts. Furthermore, we will thoroughly and systemically reveal the molecular mechanisms of food-derived GGPP in restricting the therapeutic efficacy of statins. This study is promising to provide a novel biochemical index or guide for the proper and effective use of statin medication and to reassess the therapeutic value of statins in treating pulmonary hypertension.

他汀通过抑制内源性胆固醇合成、配合控制食物中外源性胆固醇摄入对心血管疾病具有显著疗效。细胞和动物实验证明他汀可有效治疗肺动脉高压等疾病，但临床研究却出现与细胞/动物实验不一致的矛盾窘况。他汀药理作用的另一关键环节是抑制内源性GGPP生成，而目前尚无任何针对体内GGPP水平与他汀疗效的相关研究。申请人预实验发现食物源性GGPP对大鼠体内GGPP稳态产生显著影响，因此有可能成为他汀在临床研究中无法重现细胞/动物实验具有疗效的重要原因。本项目拟运用已成功建立的GGPP检测等技术，系统观察日常食物对大鼠GGPP水平的影响；研究外源性GGPP摄入对肺动脉高压形成的作用及其对他汀疗效的限制；确认GGPP天然拮抗剂可否解除这种限制；并揭示GGPP影响他汀疗效的分子机制。本项目有望为他汀类药物的应用提供一项必要的生化监测指标，为重新定位他汀对相关疾病的治疗价值提供临床前的理论依据。

本项目研究发现食物源性GGPP 摄入可影响血浆GGPP 稳态，深入的机制探讨阐明了食物源性GGPP可干扰他汀对缺氧诱导RhoA活化→ROCK2磷酸化→CaSR和HIMF基因表达增强、缺氧诱导→Rab10激活→Rab10协同CaSR膜转位这两条信号通路的抑制，进而拮抗他汀治疗肺动脉高压的机理。该研究不仅揭示了他汀类药物治疗肺动脉高压的干扰因素，阐明了他汀在细胞及动物实验中治疗肺动脉高压与临床观察的疗效不一致的机制，还提示限制食物源性GGPP摄入，或者应用GGPP的天然拮抗剂可以确保他汀发挥疗效。研究成果有望重新定义他汀对肺动脉高压的治疗价值，也为他汀在其他疾病中的有效运用提供了理论依据和新的研究思路。