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Updated: May 28, 2026
Quantification of Atherosclerosis in Mice
Published on: June 12, 2019
Effects of bulevirtide on atherosclerosis in an ApoE-deficient mouse model
Jonas Rusnak1,2, Victoria Delcheva1,2, Dirk Theile3
1Department of Cardiology, Angiology and Pneumology, Heidelberg University, Medical Faculty Heidelberg/Heidelberg University Hospital Internal Medicine III, Heidelberg, Germany.
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.
Insights
Dual inhibition of bile acid transporters sodium taurocholate co-transporting polypeptide (NTCP) and organic anion transporting polypeptide (OATP) significantly increased bile acid levels in mice. This dual inhibition also reduced macrophage content in atherosclerotic lesions, suggesting a role for bile acids in modulating plaque composition.
Area of Science:
- Cardiovascular Research
- Hepatology
- Pharmacology
Background:
- Bile acids play a crucial role in lipid metabolism and have demonstrated effects on atherosclerosis.
- Dysregulation of bile acid homeostasis is implicated in various metabolic and cardiovascular diseases.
- Inhibiting specific bile acid transporters, such as NTCP and OATP, offers a potential therapeutic strategy.
Purpose of the Study:
- To investigate the impact of inhibiting sodium taurocholate co-transporting polypeptide (NTCP) with bulevirtide and organic anion transporting polypeptide (OATP) with rifampicin, individually and in combination, on bile acid levels and atherosclerosis.
- To evaluate the therapeutic potential of dual transporter inhibition in a mouse model of atherosclerosis.
Main Methods:
- Apolipoprotein E-deficient (ApoE⁻/⁻) mice on a Western diet were treated daily for four weeks with bulevirtide, rifampicin, a combination of both, or vehicle.
- Plasma bile acids and lipids were measured.
- Atherosclerotic lesion size and macrophage content in the aortic sinus were quantified.
Main Results:
- While plasma lipid profiles and atherosclerotic lesion sizes remained unchanged, both bulevirtide and rifampicin significantly increased plasma bile acid concentrations.
- The combination therapy resulted in the most substantial increase in bile acid levels, indicating additive effects.
- Combined NTCP and OATP inhibition altered the macrophage-to-lesion area ratio, suggesting an impact on plaque composition.
Conclusions:
- Combined inhibition of NTCP and OATP significantly elevated bile acid levels in ApoE⁻/⁻ mice.
- Despite no change in lesion size, dual transporter inhibition modulated plaque composition by reducing macrophage content.
- These findings underscore the association between bile acids and the modulation of atherosclerotic plaque characteristics, presenting a potential therapeutic avenue.