Chronic inhibition of farnesyl pyrophosphate synthase improves endothelial function in spontaneously hypertensive rats.

Farnesyl pyrophosphate synthase (FPPS, EC 2.5.1.10), an essential enzyme in the mevalonate pathway, catalyzes the synthesis of isoprenoid intermediates. The isoprenoid intermediates are needed for protein isoprenylation of RhoA for its function on regulation of endothelial nitric oxide synthase (eNOS). We previously reported that FPPS were upregulated in spontaneously hypertensive rats (SHR) when compared with Wistar-Kyoto rats (WKY), and this was accompanied by development of endothelial dysfunction. Five-week-old male rats were daily gavaged with vehicle or an FPPS inhibitor (alendronate, 1 or 10mg/kg). After 12-week administration of alendronate, endothelium-dependent and -independent vasorelaxation were measured in isolated aortic rings. Twelve-week of alendronate (10mg/kg/day) treatment restored the impaired endothelium-dependent vasodilation in SHR. Furthermore, long-term treatment with an FPPS inhibitor significantly suppressed RhoA activation and increased phospho-eNOS/eNOS ratio. In conclusion, chronic treatment with an FPPS inhibitor improves the endothelial function in SHR, and the upregulation of phospho-eNOS/eNOS ratio with inhibition of RhoA activation may be an important mechanism.