Role Of Cystathionine Beta-Synthase In Stress-Induced Hyperhomocysteinemia And Its Regulatory Mechanism

It is confirmed that cardiovascular system is an important target of stress effect. In previous study, it was found that stress increased the level of plasma horhocysteine in rat. To clarify the mechanism and molecular basis of stress-induced hyperhomocysteinemia, the present study is designed to investigate the influence of stress on cystathionine beta-synthase (CBS), the key enzyme involved in homocysteine transsulfurati9n process, and probe the role of CBS in homocysteine metabolism of the stressed rats and the mechanism of stress-induced CBS changes. The results showed that the disorder of transsulfuration metabolism was the main regulatory pathway in stress-induced hyperhomocysteinemia, in which liver acted as the predominant locus. The development of hyperhomocysteinemia was mainly derived from a reduction in hepatic CBS activities which was accompanied with a significant decrease in its mRNA level. Further research showed that expression of Sp3, a negative factor for CBS transcription, was increased in hepatocytes of stressed rats, which decreased the activity of a positive transcription factor for CBS, Spl, by competitive binding. Thus CBS transcription was inhibited. The ratio of Spl to Sp3 was the key point of stress-regulated CBS transcription. It was also found that glucocorticoids, one of important stress hormones, enhanced the binding of glucocorticoids receptor and the regulatory region of Sp3 promoter. As a result, Sp3 activity was increased, while Spl activity was lowered. It in turn led to the decreaseof cbs transcription and CBS activity. Besides, over-secreted adrenaline and noradrenaline during stress resulted in the increase of IL-6 level in serum of stressed rat by activating P -adrenaline receptor. Subsequently IL-6 activated NF- B and enhanced Sp3 activity, which inhibited cbs transcription and CBS activity. Finally the disorder of homocysteine metabolism happened. The results suggest that stress induces hyperhomocysteinemia. The glucocorticoids and (nor)adrenaline-mediated IL-6 pathway play important role in regulation of hepatic homocysteine transsulfuration pathway catalyzed by CBS. The decrease of CBS catalytic activity may be the biological basis for stress-injured cardiac function. The study provides new scientic data for recognizing the molecular mechanism of stress-induced cardiovascular diseases and etiology of hyperhomocysteinemia.