In Vivo Evidence of Enhancement of HGF-induced Angiogenesis by Fluvastatin

Currently, therapeutic angiogenesis using gene transfer of angiogenic growth factors has entered the realm of novel therapy for patients with critical limb ischemia. However, its clinical utility might be enhanced by combination with classical pharmacological approaches. Thus, in this study, we examined adjunctive therapy to enhance the angiogenic ef- fects of gene transfer, with HMG-CoA reductase inhibitors, statins, which have pleiotropic vascular-protective effects. Here, we evaluated the effects of a combination of hepatocyte growth factor (HGF) gene therapy with fluvastatin in a mouse hindlimb ischemia model. Hindlimb ischemia model mice were given a normal diet, high-cholesterol diet (HCD) or HCD with fluvastatin, after in- tramuscular injection of human HGF plasmid DNA. Intramuscular injection of HGF plasmid into ischemic limbs signifi- cantly increased blood flow and capillary density. However, HCD diminished the increase in blood flow and capillary density induced by HGF gene transfer. Administration of fluvastatin significantly attenuated the reduction in blood flow and decrease in capillary density, while it did not change the serum cholesterol level. Overall, these results demonstrated that fluvastatin significantly enhanced the increase in blood flow and capillary density induced by HGF gene transfer in a hindlimb ischemia mouse model with HCD, through a non-cholesterol-lowering effect. Clinical use of fluvastatin might be possible adjunctive therapy to enhance therapeutic angiogenesis.