The Influence Of Hyperhomocysteinemia On Vascular Endothelial Function And Inflammation/antagonizing Effect Of Simvastatin

Background and Objective Hyperhomocysteinemia(Hhcy) is an independent risk factor for atherosclerosis(AS), but the mechanisms of homocysteine(hcy)-mediated vascular pathogenesis remain largely unknown. Endothelial injury and dysfunction is considered key factor to the development of atherosclerotic vascular diseases, some in vitro experiments demonstrated that vascular endothelium-dependent relaxation could be impaired when incubated with hcy. On injury, endothelial cells are capable of producing chemokines that participate in inflammatory reactions in the arterial wall. It has been reported that hcy can induce interleukin-8(IL-8) when incubated with endothelial cells, but whether Hhcy could induce similar result in vivo need to be studied. Statins are widely used in patients with AS and claimed to improve endotheilal-dependent relaxation and have anti-inflammation activities independent of plasma cholesterol lowering, but the effects of statins on vascular damage induced by Hhcy are seldom investigated. In the present study, Hhcy will be induced by 12 weeks methionine-rich diet, then we will investigate the influence of Hhcy on vascular endothelial function and inflammation, in addition we will investigate whether simvastatin could ameliorate the damage induced by Hhcy.Methods Twenty one New Zealand white rabbit were randomly divided into three group , control group (C n=6) were fed with standard rabbit diet ,methionine (M n=8) were fed with 1.7%methionine diet, simvastatin group ( S n=7) were fed with 1.7%methionine diet and simvastatin (5mg ·kg^-1· d^-1). After 12 weeks, the level of hcy in plasma were measured by HPLC, endothelial dependent vasodilation and endothelial independent vasodilation were measured in isolated thoracic aorta, furthermore, it was also observed whether the relaxing effect was modulated by N^G-nitro-L-argine(L-NNA). The expression of endothelial nitric oxide synthase (eNOS) were studied by immunohistochemistry, levels of nitric oxide(NO) in serum and tissue were determined.IL-8 in serum and tissue were determined by ELISA , the expression and activation of nuclear factor- k B (NF- k B) were studied by immunohistochemistryoResults Hhcy was induced after methionine-rich diet. Hhcy induced significant inhibition on endothelial dependent vasodilation to acetylcholine, but had no effect on endothelial independent vasodilation to nitroglycerine. Simvastatin attenuated the impairment of homocysteine on endothelial function, L-NNA preincubating abolished effect of simvastatin. In addition , the eNOS immunoreactivity and production of NO were declined in methionine group, while simvastatin restored eNOS immunoreactivity and increased production of NO. The production of IL-8 and activation of NF- k B were increased in methionine group 0 Simvastatin inhibited hey -induced production of IL-8 and activation of NF- k BoConclusion 1. Hhcy could be indued after methionine-rich diet. 2. Hhcy could induce endothelial dysfunction by inhibiting expression of eNOS and production of NO. Furthermore, Hhcy induce activation of NF- k B and consequently enhances the production of IL-8. 3. Simvastatin can ameliorate Hhcy - induced endothelial damage ,this beneficial effect may relate to promote expression of eNOS and increase bioavailability of NO, inhibit activation of NF- k B and production of IL-8.