The Beneficial Effect of Lomitapide on the Cardiovascular System in LDLr^-/- Mice with Obesity

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 & PLUSMN; 1.5 vs. 40.3 & PLUSMN; 1.8 g), % of fat mass (41.6 & PLUSMN; 1.9% vs. 31.8 & PLUSMN; 1.7%), blood glucose (215.5 & PLUSMN; 21.9 vs. 142.3 & PLUSMN; 7.7 mg/dL), and lipid levels (cholesterol: 600.9 & PLUSMN; 23.6 vs. 451.7 & PLUSMN; 33.4 mg/dL; LDL/VLDL: 250.6 & PLUSMN; 28.9 vs. 161.1 & PLUSMN; 12.24 mg/dL; TG: 299.5 & PLUSMN; 24.1 vs. 194.1 & PLUSMN; 28.1 mg/dL) were significantly decreased, and the % of lean mass (56.5 & PLUSMN; 1.8% vs. 65.2 & PLUSMN; 2.1%) was significantly increased in the HFD group after lomitapide treatment. The atherosclerotic plaque area also decreased in the thoracic aorta (7.9 & PLUSMN; 0.5% vs. 5.7 & PLUSMN; 0.1%). After treatment with lomitapide, the endothelium function of the thoracic aorta (47.7 & PLUSMN; 6.3% vs. 80.7 & PLUSMN; 3.1%) and mesenteric resistance artery (66.4 & PLUSMN; 4.3% vs. 79.5 & PLUSMN; 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.