Abstract
Severely elevated plasma homocysteine and methionine lead to thromboembolic events and strokes in homocystinuric (HCU) patients. Mouse models of HCU failed to exhibit prothrombotic phenotype, presumably due to lack of hypermethioninemia. We evaluated the impact of hypermethioninemia together with hyperhomocysteinemia on murine HCU phenotype and compared the efficacy of the current and novel therapies for HCU. High methionine intake decreased survival of I278T mice, which died from intestinal bleeding with hepatic and pancreatic failure. I278T mice on normal or increased methionine intake developed endothelial dysfunction, but paradoxically demonstrated delayed occlusion in an induced arterial thrombosis model. RNA-seq analysis suggested that expression of coagulation factor XI (FXI) is downregulated in livers of I278T mice. Indeed, plasma concentrations of FXI were decreased in I278T mice on normal diet and further reduced by increased methionine intake. Dietary methionine restriction normalized the observed phenotype. Similarly, treatment with OT-58, a novel enzyme therapy for HCU, corrected the phenotype in I278T mice regardless of their dietary methionine intake. Hypermethioninemia does not contribute to prothrombotic phenotype in murine HCU. Downregulation of FXI may contribute to the lack of prothrombotic tendency in I278T mice. Methionine restriction or treatment with OT-58 corrects vascular disease in the I278T mouse model of HCU.
Highlights
Elevated plasma total homocysteine (Hcy) causes endothelial dysfunction, increases thrombosis and is associated with carotid atherosclerosis, lacunar infarction and markedly increased risk of stroke in atrial fibrillation [1,2,3]
Our results suggest that severe hyperhomocysteinemia with or without hypermethioninemia disrupts production of liver-synthesized coagulation factor XI in a I278T mouse model of HCU
The exact role of elevated plasma Hcy in this process is often debated because of contradictory results from several clinical trials focused on lowering plasma homocysteine and prevention of cardiovascular outcomes [17]
Summary
Elevated plasma total homocysteine (Hcy) causes endothelial dysfunction, increases thrombosis and is associated with carotid atherosclerosis, lacunar infarction and markedly increased risk of stroke in atrial fibrillation [1,2,3]. Patients often find this diet difficult to follow, which exacerbates clinical complications [4,6] Novel enzyme therapies, such as OT-58, are in development to provide more therapeutic options and to improve metabolic control, prevent clinical symptoms and lessen or remove entirely the dietary requirements [7,8,9]. PEG-CBS or 20NHS PEG-htCBS C15S, is an engineered, recombinantly produced and chemically modified human CBS enzyme developed to reduce or normalize pathologically increased plasma. I278T mice, unlike HCU patients, do not develop profound hypermethioninemia in addition to severely elevated plasma Hcy when maintained on standard rodent chow. We developed hypermethioninemia in I278T mice by increasing their dietary Met intake and analyzed the effects of severely elevated plasma Hcy and Met on endothelial function and thrombosis.
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