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Cystathionine β-synthase deficiency: different changes in proteomes of thrombosis-resistant Cbs-/- mice and
Marta Sikora1, Izabela Lewandowska1, Łukasz Marczak1
1European Centre for Bioinformatics and Genomics, Institute of Bioorganic Chemistry, 61-704, Poznan, Poland.
Insights
Cystathionine β-synthase deficiency causes thrombosis in humans but not mice. Plasma proteome analysis revealed distinct differences in coagulation and complement pathways, suggesting mice have better adaptive responses to hyperhomocysteinemia.
Area of Science:
- Biochemistry
- Proteomics
- Molecular Biology
Background:
- Cystathionine β-synthase (CBS) deficiency is linked to vascular thrombosis in humans.
- Cystathionine β-synthase deficient (Cbs-/-) mice do not exhibit blood coagulation abnormalities.
- Disparate thrombotic phenotypes between human patients and mouse models necessitate molecular investigation.
Purpose of the Study:
- To identify the molecular basis for differing thrombotic phenotypes in CBS-deficient humans and mice.
- To compare plasma proteomes of CBS-deficient individuals and Cbs-/- mice with their respective controls.
Main Methods:
- Label-free mass spectrometry was employed to analyze plasma proteomes.
- Comparative proteomic analysis was performed on Cbs-/- mice and CBS-/- humans versus wild-type controls.
- Ingenuity Pathways Analysis (IPA) was used to identify affected canonical pathways.
Main Results:
- 117 differentiating plasma proteins were identified in Cbs-/- mice and 41 in CBS-/- humans.
- Sixteen of 21 shared differentiating proteins showed opposite expression patterns between species.
- Proteins involved in coagulation and complement cascades were more prevalent in CBS-/- humans (51%) than in Cbs-/- mice (21%).
- Canonical pathways like LXR/RXR, FXR/RXR activation, and atherosclerosis signaling were similarly affected in both models.
- The Coagulation System was more strongly affected in CBS-/- humans, while the acute phase response and complement system were more affected in Cbs-/- mice.
Conclusions:
- Differences in plasma proteomes, particularly in the Coagulation System, may explain the contrasting thrombotic phenotypes.
- Cbs-/- mice exhibit a more effective adaptive response to hyperhomocysteinemia compared to CBS-/- humans.
- These findings highlight species-specific adaptations in response to CBS deficiency.
Abstract:
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.
