Interference in mevalonate pathway ameliorates homocysteine-induced endothelium-dysfunction

Abstract

Homocysteine is a risk factor for atherosclerosis and hypertension and induces endothelium-dysfunction. Accumulation of cholesterol and reactive oxygen species plays a key role in the endothelium-dysfunction. This study investigated the hypothesis of an involvement of mevalonate pathway and oxidative pathway in homocysteine-induced endothelial damage. Homocysteine induced impairment of the endothelium-dependent vasorelaxation of rat aortic rings by isometric tension, while it also reduced the nitric oxide level and the nitric oxide synthase activity in human umbilical vein endothelial cells, followed by accumulation of superoxide anion and cholesterol. However, the level of asymmetric dimethylarginine remained unaffected by homocysteine. The adverse effect of homocysteine on endothelial function was found to be partially enhanced either by squalestatin-reducing cholesterol or by superoxide dismutase-reducing superoxide anion. Moreover, this effect of homocysteine could be completely ameliorated by simvastatin, very similar to that of cotreatment of squalestatin and superoxide dismutase. Respectively, mevalonolactone partly or squalene fully attenuated the effect of simvastatin or squalestatin on homocysteine-induced endothelial dysfunction. In conclusion, our results suggested that the mevalonate pathway mediates homocysteine-induced endothelium dysfunction besides the oxidative pathway. Interference in the mevalonate pathway and oxidative pathway provides effective protection of endothelial function.