P564L-cystathionine metabolism by cystathionine gamma lyase generates H2S to preserve endothelial cell function and decelerate atherosclerosis development in humans

Funding Acknowledgements: ESC Bas Res Fel 2016, ESC R-2016-054 to S.I.B., SFB 815/A6 and Exzellenzcluster 147 to I.F., SFB 815/A7 to J.P. Background: L-cystathionine is selectively catabolized by cystathionine g lyase (CSE) to produce hydrogen sulfide (H2S) which has been identified as an important regulator of vascular function. In the present study endothelial CSE regulation and function during atherosclerosis development were evaluated. Results: CSE expression was largely upregulated in a Krüppel-like factor (KLF) 2/ miR-27b dependent manner in endothelial cells of atheroprone regions of murine aortas and human atheromas compared to healthy human arteries. Although CSE was upregulated, circulating and intra-plaque H2S levels as well as circulating CSE substrate levels; L-cystathionine; were reduced in patients compared to healthy subjects, indicating reduced CSE activity. This was an effect of CSE phosphorylation on the inhibitory Ser377 in response to inflammatory stimuli. Endothelial cell-specific CSE deletion reduced H2S bioavailability by 70%, increased 5-fold L-cystathionine circulating levels and resulted in endothelial cell dysfunction in murine aortas, elevated monocyte adhesion and accelerated atherosclerosis. Overall, reduced H2S bioavailability in the murine and human vascular wall resulted in the loss of sulfhydration of the RNA binding protein HuR, which potentiated the homodimerization of HuR and its capacity to bind to the 3’ UTR of its targets CD62E and CTSS.