PloS one · 2026
Effects of bulevirtide on atherosclerosis in an ApoE-deficient mouse model.
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Rusnak Jonas, Delcheva Victoria, Theile Dirk, Blank Antje, Frey Norbert, Preusch Michael R
Аннотация
OBJECTIVE: Bile acids are known to have a positive impact on atherosclerosis. The study investigates the impact of sodium taurocholate co-transporting polypeptide (NTCP) inhibition with bulevirtide, organic anion transporting polypeptide (OATP) inhibition with rifampicin, and their combination on bile acid levels and atherosclerosis in apolipoprotein E-deficient (ApoE⁻/⁻) mice.
METHODS: Fifty-six female ApoE⁻/⁻ mice on a Western type diet were treated daily for four weeks with bulevirtide (5 mg/kg), rifampicin (20 mg/kg), a combination of both, or vehicle. Plasma bile acids and lipids were measured at sacrifice. Atherosclerotic lesion size was quantified in the aortic sinus, and macrophage content was analyzed by Mac-2 immunohistochemistry.
RESULTS: Plasma cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglyceride levels remained unchanged across all groups, being accompanied with no changes of atherosclerotic lesion size (p = 0.896). However, treatment with bulevirtide (p = 0.017), rifampicin (p = 0.003), but mostly their combination (p < 0.001) significantly increased plasma bile acid concentrations and altered the macrophage-to-lesion area ratio, at least for the combination therapy group (p = 0.020). The combined treatment exhibited the highest bile acid levels, indicating additive effects of dual transporter inhibition.
CONCLUSIONS: While lesion sizes remained unaffected, the combined NTCP and OATP inhibition significantly enhanced bile acid levels and reduced macrophage content in early atherosclerotic lesions of ApoE⁻/⁻ mice. These results highlight the association of bile acid with the modulation of plaque composition as a potential therapeutic mode of action.
METHODS: Fifty-six female ApoE⁻/⁻ mice on a Western type diet were treated daily for four weeks with bulevirtide (5 mg/kg), rifampicin (20 mg/kg), a combination of both, or vehicle. Plasma bile acids and lipids were measured at sacrifice. Atherosclerotic lesion size was quantified in the aortic sinus, and macrophage content was analyzed by Mac-2 immunohistochemistry.
RESULTS: Plasma cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglyceride levels remained unchanged across all groups, being accompanied with no changes of atherosclerotic lesion size (p = 0.896). However, treatment with bulevirtide (p = 0.017), rifampicin (p = 0.003), but mostly their combination (p < 0.001) significantly increased plasma bile acid concentrations and altered the macrophage-to-lesion area ratio, at least for the combination therapy group (p = 0.020). The combined treatment exhibited the highest bile acid levels, indicating additive effects of dual transporter inhibition.
CONCLUSIONS: While lesion sizes remained unaffected, the combined NTCP and OATP inhibition significantly enhanced bile acid levels and reduced macrophage content in early atherosclerotic lesions of ApoE⁻/⁻ mice. These results highlight the association of bile acid with the modulation of plaque composition as a potential therapeutic mode of action.