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

Cystathionine 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.

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