法尼基焦磷酸合成酶调控小G蛋白参与损伤后血管重构的作用及机制研究

Vascular smooth muscle cells(VSMCs)、the small GTP proteins activation and the imbalances between MMPS/TIMPS play an important role in the process of vascular remodeling after injury. Our previous work observed an elevated farnesyl pyrophosphate synthase (FPPS) expression in the carotid artery after balloon injury and in angiotensinII and norepinephrine-induced VSMCs.Inhibition of FPPS attenuates VSMCs proliferation and fibrotic responses through interfering with small GTP proteins such as RhoA and Ras.However, whether FPPS participates in the process of vascular remodeling after injury and the underlying mechanisms remains to be determined. Based on our previous results, using lentivirus-mediated siRNA gene silencing or adenovirus- mediated gene overexpression of the target gene FPPS, the project intended to explore its role in vascular remodeling through modulating small G proteins activation and the imbalance between MMPS/TIMPS in the carotid artery after balloon injury. The project will provide a scientific basis for exploring new mechanisms and new strategies for prevention of vascular remodeling.

血管平滑肌细胞激活、小G蛋白活化、基质金属蛋白酶(matrix metalloproteinases，MMPs)与组织基质金属蛋白酶抑制剂(tissue inhibitors of MMPs，TIMPs)失衡在损伤后血管重构过程中扮演重要角色。课题组前期研究发现法尼基焦磷酸合成酶(farnesyl pyrophosphate synthase, FPPS)在球囊损伤后大鼠颈动脉血管组织中及在血管紧张素II、去甲肾上腺素刺激的血管平滑肌细胞中表达明显升高。干预FPPS可以通过调控小G蛋白抑制血管平滑肌细胞增殖及纤维化反应。但FPPS是否调控小G蛋白通路参与血管重构过程及其机制尚不清楚。本项目拟利用慢病毒载体及腺病毒载体对目的基因FPPS进行基因沉默或过表达，试图论证FPPS可能通过调控小G蛋白进而调控MMPS/TIMPS平衡参与血管重构，为防治血管重构提供新的靶分子。

血管平滑肌细胞激活、小G蛋白活化、基质金属蛋白酶(matrix metalloproteinases，MMPs)与组织基质金属蛋白酶抑制剂(tissue inhibitors of MMPs，TIMPs)失衡在损伤后血管重构过程中扮演重要角色。本研究发现，利用血管损伤因子AngⅡ、TGF-β1刺激VSMCs后，FPPS表达明显上调，利用FPPS抑制剂伊班膦酸钠或采用慢病毒干扰FPPS表达，可改善VSMCs增殖、迁移和CTGF的表达，其可能的机制为涉及RhoA活性的调节，以及p38和JNK信号通路。类似地，球囊损伤后颈动脉中FPPS表达明显上调，通过Lenti-FPPS shRNA血管腔内给药能抑制新生内膜中平滑肌细胞增殖、血管狭窄系数（NA/MA），同时下调CTGF表达、小G蛋白RhoA、RAC1活性，证实通过Lenti-FPPS shRNA能抑制新生内膜增生，抑制血管再狭窄，其可能机制为可能调节RhoA、RAC1活性。上述研究结果提示FPPS在血管重构中起重要作用，利用慢病毒载体对目的基因FPPS进行基因沉默改善损伤后血管重构，为防治血管重构提供新的靶分子。