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The Beneficial Effect of Lomitapide on the Cardiovascular System in LDLr-/- Mice with Obesity
Undral Munkhsaikhan1,2, Young In Kwon1, Amal M Sahyoun1,3
1Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Insights
Lomitapide treatment significantly improved cardiovascular function and lipid profiles in LDL receptor-knockout mice. This study demonstrates lomitapide
Area of Science:
- Cardiovascular Research
- Metabolic Diseases
- Pharmacology
Background:
- Homozygous familial hypercholesteremia (HoFH) is a severe genetic disorder leading to premature death from cardiovascular events.
- Lomitapide is an FDA-approved therapy for HoFH, but its effects in preclinical models require further definition.
Purpose of the Study:
- To investigate the therapeutic effects of lomitapide on cardiovascular function in a mouse model of HoFH.
- To evaluate lomitapide's impact on lipid profiles, body composition, and vascular health in LDL receptor-knockout (LDLr-/-) mice.
Main Methods:
- LDLr-/- mice were fed a high-fat diet (HFD) and treated with lomitapide (1 mg/Kg/Day) for two weeks.
- Assessed body weight, body composition, blood glucose, lipid profiles, and atherosclerotic plaque area.
- Determined vascular reactivity and endothelial function in thoracic aorta and mesenteric resistance arteries.
Main Results:
- Lomitapide treatment significantly reduced body weight, fat mass, blood glucose, and lipid levels (cholesterol, LDL/VLDL, TG) in HFD-fed LDLr-/- mice.
- Atherosclerotic plaque area in the thoracic aorta was significantly decreased.
- Endothelial function in both conductance and resistance arteries was improved, correlating with reduced vascular ER stress, oxidative stress, and inflammation.
Conclusions:
- Lomitapide treatment effectively improves cardiovascular function, lipid profiles, and reduces inflammatory markers in a mouse model of HoFH.
- These findings support the beneficial role of lomitapide in mitigating cardiovascular complications associated with severe hypercholesterolemia.
Objectives:
Homozygous familial hypercholesteremia (HoFH) is a rare, life-threatening metabolic disease, mainly caused by a mutation in the LDL receptor. If untreated, HoFH causes premature death from acute coronary syndrome. Lomitapide is approved by the FDA as a therapy to lower lipid levels in adult patients with HoFH. Nevertheless, the beneficial effect of lomitapide in HoFH models remains to be defined. In this study, we investigated the effect of lomitapide on cardiovascular function using LDL receptor-knockout mice (LDLr-/-).
Methods:
Six-week-old LDLr-/- mice were fed a standard diet (SD) or a high-fat diet (HFD) for 12 weeks. Lomitapide (1 mg/Kg/Day) was given by oral gavage for the last 2 weeks in the HFD group. Body weight and composition, lipid profile, blood glucose, and atherosclerotic plaques were measured. Vascular reactivity and markers for endothelial function were determined in conductance arteries (thoracic aorta) and resistance arteries (mesenteric resistance arteries (MRA)). Cytokine levels were measured by using the Mesoscale discovery V-Plex assays.
Results:
Body weight (47.5 ± 1.5 vs. 40.3 ± 1.8 g), % of fat mass (41.6 ± 1.9% vs. 31.8 ± 1.7%), blood glucose (215.5 ± 21.9 vs. 142.3 ± 7.7 mg/dL), and lipid levels (cholesterol: 600.9 ± 23.6 vs. 451.7 ± 33.4 mg/dL; LDL/VLDL: 250.6 ± 28.9 vs. 161.1 ± 12.24 mg/dL; TG: 299.5 ± 24.1 vs. 194.1 ± 28.1 mg/dL) were significantly decreased, and the % of lean mass (56.5 ± 1.8% vs. 65.2 ± 2.1%) was significantly increased in the HFD group after lomitapide treatment. The atherosclerotic plaque area also decreased in the thoracic aorta (7.9 ± 0.5% vs. 5.7 ± 0.1%). After treatment with lomitapide, the endothelium function of the thoracic aorta (47.7 ± 6.3% vs. 80.7 ± 3.1%) and mesenteric resistance artery (66.4 ± 4.3% vs. 79.5 ± 4.6%) was improved in the group of LDLr-/- mice on HFD. This was correlated with diminished vascular endoplasmic (ER) reticulum stress, oxidative stress, and inflammation.
Conclusions:
Treatment with lomitapide improves cardiovascular function and lipid profile and reduces body weight and inflammatory markers in LDLr-/- mice on HFD.
