Abstract 278: Enhanced Cystathionine ß-Synthase Nitration in Diet-Induced Hyperhomocysteinemic Rats Accelerates the Progression of Hyperhomocysteinemia

Hyperhomocysteinemia is an independent risk factor for cardiovascular diseases,which may be caused by genetic deficiencies in enzymes responsible for remethylation or transsulfuration of homocysteine, nutritional deficiencies in vitamins, or excessive intakes of methionine. Since transsulfuration pathway is the only irreversible pathway in homocysteine metabolism, its key enzyme cystathionine β-synthase is vital in terminal removement of homocysteine. In addition, Studies have observed that enhanced nitrative stress in hyperhomocysteinemic rats could induce cardiovascular injuries, and peroxynitrite stimulation in vitro resulting in decreased bioactivity of cystathionine β-synthase. Therefore, to determine the contribution of nitrative stress to progression of hyperhomocysteinemia, and how it is related to cystathionine β-synthase, we used three groups of rats (Con with normal diet, HHcy with 2.5% methionine diet, HHcy+FeTMPyP with 2.5% methionine diet +FeTMPyP) to observe the effects of nitrative stress on cystathionine β-synthase. Results showed that in diet-induced hyperhomocysteinemic rats, tHcy levels and nitrative stress increased, surprisingly, pretreatment with peroxynitrite scavenger FeTMPyP ameliorated the level of tHcy as well as nitrative stress. Further experiments showed cystathionine β-synthase bioactivity in HHcy rats was less potent than other groups yet described, and the level of cystathionine β-synthase nitration was the most significant,while the entire trends reversed after FeTMPyP pretreatment. In conclusion, these results highlight for the first time that in diet-induced hyperhomocysteinemic rats, cystathionine β-synthase bioactivity reduction is not just a traditional etiologic factor, but rather an outcome of hyperhomocysteinemia, and resulting from the high level of nitrative stress caused by hyperhomocysteinemia, the cystathionine β-synthase nitration plays a mutual role in hyperhomocysteinemia development via causing the metabolic disorder of homocysteine. These findings may shed a novel light on the homocystine-lowering target of hyperhomocysteinemia.