The interaction of estrogen and CSE/HS pathway in the development of atherosclerosis.

Both estrogen and hydrogen sulfide (HS) have been shown to inhibit the development of atherosclerosis. We previously reported that cystathionine γ-lyase knockout (CSE-KO) male mice develop atherosclerosis earlier than male wild-type (WT) mice. The present study investigated the interaction of CSE/HS pathway and estrogen on the development of atherosclerosis in female mice. Plasma estrogen levels were significantly lower in female CSE-KO mice than in female WT mice. NaHS treatment had no effect on plasma estrogen levels in both WT and CSE-KO female mice. After CSE-KO and WT female mice were fed with atherogenic diet for 12 wk, plasma lipid levels were significantly increased and triglyceride levels decreased compared with those of control diet-fed mice. Atherogenic diet induced more atherosclerotic lesion, oxidative stress, intracellular adhesion molecule-1 (ICAM-1), and NF-κB in CSE-KO mice than in WT mice. Estrogen treatment of atherogenic diet-fed WT mice attenuated hypercholesterolemia, oxidative stress, ICAM-1 expression, and NF-κB in WT mice but not in atherogenic diet-fed CSE-KO mice. Furthermore, HS production in both the liver and vascular tissues was enhanced by estrogen in WT mice but not in CSE-KO mice. It is concluded that the antiatherosclerotic effect of estrogen is mediated by CSE-generated HS. This study provides new insights into the interaction of HS and estrogen signaling pathways on the regulation of cardiovascular functions. Female cystathionine γ-lyase (CSE)-knockout mice have significantly lower plasma estrogen levels and more severe early atherosclerotic lesion than female wild-type mice. HS production in liver and vascular tissues is enhanced by estrogen via its stimulatory effect on CSE activity. The antiatherosclerotic effect of estrogen is mediated by CSE-generated HS.