Cystathionine β-synthase deficiency: different changes in proteomes of thrombosis-resistant Cbs−/− mice and thrombosis-prone CBS−/− humans

Abstract

AbstractCystathionine β-synthase (CBS)-deficient patients are prone to vascular thrombosis. In contrast, Cbs−/− mice show no abnormalities in blood coagulation. To identify molecular basis underlying these disparately different thrombotic phenotypes, we analyzed plasma proteomes of Cbs−/− vs. Cbs+/+ mice (8-month-old, 12/group, sex-matched) and CBS−/− vs. CBS+/+ humans (37 ± 7-year-old, 10–14/group, sex-matched) using label-free mass spectrometry. We identified 117 and 41 differentiating plasma proteins in Cbs−/− mice and CBS−/− humans, respectively. Twenty-one proteins were shared between CBS−/− humans and Cbs−/− mice, with sixteen changed in the opposite direction. Proteins involved in blood coagulation and complement/coagulation cascades represented a greater fraction of the differentiating proteins in CBS−/− patients (51%) than in Cbs−/− mice (21%). Top canonical pathways, identified by Ingenuity Pathways Analysis, such as LXR/RXR, FXR/RXR activation (− log[P-value] = 30–31) and atherosclerosis signaling (− log[P-value] = 10–11) were similarly affected in Cbs−/− mice and CBS−/− humans. The Coagulation System was affected stronger in CBS−/− humans than in Cbs−/− mice (− log[P-value] = 15 vs. 10, respectively) while acute phase response and complement system were affected stronger in Cbs−/− mice (− log[P-value] = 33 and 22, respectively) than in humans (− log[P-value] = 22 and 6, respectively). Other pathways, including IL-7 signaling and B cell development were affected only in Cbs−/− mice. Taken together, our findings suggest that differences in these processes, in particular in the Coagulation System, could account for the thrombotic phenotype in CBS−/− patients and the absence of thrombosis in Cbs−/− mice. Overall, our findings suggest that Cbs−/− mice have a better adaptive response to protect from prothrombotic effects of hyperhomocysteinemia than CBS−/− humans.