EP01 A stinky remedy for atherosclerosis

Abstract

Being the last key enzyme of the reverse trans-sulfuration pathway, cystathionine gamma-lyase (CSE) catalyzes the conversion of cystathionine into cysteine, α-ketobutyrate, and ammonia. It further catalyzes cysteine into a gasotransmitter H2S [1] . CSE-mediated H2S production affects lipid metabolism and cardiovascular health, which is exemplarily manifested in the pathogenesis of atherosclerosis [2] . In order to identify the role of endogenous H2S in the development of atherosclerosis, we tried to feed CSE deficient (CSE-KO) mice with a high fat diet as an atherosclerosis model. The control diet for this treatment is the cysteine-limited casein based rodent diet. With this control diet, CSE-KO mice showed growth retardation, decreased cysteine, H2S, and glutathione levels, and increased plasma homocysteine level. None of the CSE-KO mice survived with the cysteine-limited diet. Supplementation of cysteine, but not NaHS, to the animals sustained their lives [3] . The linkage between cysteine biosynthesis and CSE deficiency for life sustainability is thus established [3] , [4] . In the following studies, cysteine had been added to control chow or atherogenic paigen-type diet to feed CSE-KO and WT mice for 12 weeks. While WT mice and CSE-KO mice did not develop any atherosclerosis with the control chow, CSE-KO mice fed with atherogenic diet developed early fatty streak lesions in the aortic root. We further show that increased atherosclerotic lesion formation in CSE-KO mice was associated with elevated plasma cholesterol and LDL-cholesterol levels, enhanced aortic cell proliferation and oxidative stress as well as increased adhesion molecule expression. Supplementation of NaHS to the animals significantly reversed the atherosclerosis development. The mice with double knockout of CSE and apolipoprotein E (apoE) gene expression exhibited more severe atherosclerosis than CSE or apoE knockout alone [5] . Our results demonstrate that a physiological level of endogenous H2S limits the development of atherosclerosis by reducing vessel intimal proliferation and inhibiting adhesion molecule expression, and that the down-regulation of CSE/H2S system predisposes vascular tissues to vascular remodelling and early development of atherosclerosis. We may now claim that H2S is a stinky remedy for atherosclerosis [2] .