Farnesyl pyrophosphate synthase promotes restenosis after vascular injury by activating small G proteins.

This study aimed to investigate the role of farnesyl pyrophosphate synthase (FPPS) in restenosis following vascular injury. Primary vascular smooth muscle cells were transfected with or without Lenti-FPPS shRNA and subsequently stimulated with angiotensin II (10(-7) mol/l) or transforming growth factor-beta 1 (10 ng/ml). The activities of small G proteins were assessed. An in vivo vascular restenosis model was established by inducing balloon injury in the rat carotid intima. Injured carotid arteries were transfected with Lenti-FPPS shRNA (6 × 10(8) plaque-forming unit), and vascular histopathology was analyzed. Gene and protein expression levels were evaluated in both in vivo and in vitro models using quantitative RT-PCR and Western blotting, respectively. Angiotensin II or transforming growth factor-beta 1 stimulation increased the protein levels of FPPS, connective tissue growth factor, phosphorylated p38, and Jun NH2-terminal kinase, as well as the activities of small G proteins in vascular smooth muscle cells. These effects were significantly attenuated following Lenti-FPPS shRNA transfection. In the carotid artery injury model, rats exhibited luminal narrowing, extensive neointima formation, and abundant foam cells and fibrous connective tissue in the intima and media. However, these pathological changes, along with the upregulation of FPPS, connective tissue growth factor, and small G protein activities in the injured carotid arteries, were alleviated by FPPS inhibition via Lenti-FPPS shRNA transfection. This study demonstrates that FPPS contributes to restenosis after vascular injury, potentially by modulating the small G protein (Rac and RhoA)-Jun NH2-terminal kinase and small G protein (Rac and RhoA)-p38 mitogen-activated protein kinase signaling pathways in both in vitro and in vivo models.