The Beneficial Effect of Lomitapide on the Cardiovascular System in LDLr<sup>−/−</sup> 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 ad...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-06-01
|
| Series: | Antioxidants |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2076-3921/12/6/1287 |
| _version_ | 1797596328141783040 |
|---|---|
| author | Undral Munkhsaikhan Young In Kwon Amal M. Sahyoun María Galán Alexis A. Gonzalez Karima Ait-Aissa Ammaar H. Abidi Adam Kassan Modar Kassan |
| author_facet | Undral Munkhsaikhan Young In Kwon Amal M. Sahyoun María Galán Alexis A. Gonzalez Karima Ait-Aissa Ammaar H. Abidi Adam Kassan Modar Kassan |
| author_sort | Undral Munkhsaikhan |
| collection | DOAJ |
| description | 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<sup>−</sup>/<sup>−</sup>). Methods: Six-week-old LDLr<sup>−</sup>/<sup>−</sup> 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<sup>−</sup>/<sup>−</sup> 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<sup>−</sup>/<sup>−</sup> mice on HFD. |
| first_indexed | 2024-03-11T02:49:57Z |
| format | Article |
| id | doaj.art-a7c38969a08a46858fe0bd9ead16100e |
| institution | Directory Open Access Journal |
| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-11T02:49:57Z |
| publishDate | 2023-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj.art-a7c38969a08a46858fe0bd9ead16100e2023-11-18T09:04:05ZengMDPI AGAntioxidants2076-39212023-06-01126128710.3390/antiox12061287The Beneficial Effect of Lomitapide on the Cardiovascular System in LDLr<sup>−/−</sup> Mice with ObesityUndral Munkhsaikhan0Young In Kwon1Amal M. Sahyoun2María Galán3Alexis A. Gonzalez4Karima Ait-Aissa5Ammaar H. Abidi6Adam Kassan7Modar Kassan8Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163, USADepartment of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163, USADepartment of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163, USAFaculty of Health Sciences, University Rey Juan Carlos, 28922 Alcorcón, SpainInstituto de Química, Pontificia Universidad Católica de Valparaíso, Valparaíso 300, ChileCollege of Dental Medicine, Lincoln Memorial University, Knoxville, TN 37923, USADepartment of Bioscience Research and General Dentistry, College of Dentistry, The University of Tennessee Health Science Center, Memphis, TN 38163, USADepartment of Pharmaceutical Sciences, School of Pharmacy, West Coast University, Los Angeles, CA 91606, USADepartment of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163, USAObjectives: 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<sup>−</sup>/<sup>−</sup>). Methods: Six-week-old LDLr<sup>−</sup>/<sup>−</sup> 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<sup>−</sup>/<sup>−</sup> 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<sup>−</sup>/<sup>−</sup> mice on HFD.https://www.mdpi.com/2076-3921/12/6/1287familial hypercholesteremiaHFDlomitapidecardiovascular functionvascular reactivity |
| spellingShingle | Undral Munkhsaikhan Young In Kwon Amal M. Sahyoun María Galán Alexis A. Gonzalez Karima Ait-Aissa Ammaar H. Abidi Adam Kassan Modar Kassan The Beneficial Effect of Lomitapide on the Cardiovascular System in LDLr<sup>−/−</sup> Mice with Obesity Antioxidants familial hypercholesteremia HFD lomitapide cardiovascular function vascular reactivity |
| title | The Beneficial Effect of Lomitapide on the Cardiovascular System in LDLr<sup>−/−</sup> Mice with Obesity |
| title_full | The Beneficial Effect of Lomitapide on the Cardiovascular System in LDLr<sup>−/−</sup> Mice with Obesity |
| title_fullStr | The Beneficial Effect of Lomitapide on the Cardiovascular System in LDLr<sup>−/−</sup> Mice with Obesity |
| title_full_unstemmed | The Beneficial Effect of Lomitapide on the Cardiovascular System in LDLr<sup>−/−</sup> Mice with Obesity |
| title_short | The Beneficial Effect of Lomitapide on the Cardiovascular System in LDLr<sup>−/−</sup> Mice with Obesity |
| title_sort | beneficial effect of lomitapide on the cardiovascular system in ldlr sup sup mice with obesity |
| topic | familial hypercholesteremia HFD lomitapide cardiovascular function vascular reactivity |
| url | https://www.mdpi.com/2076-3921/12/6/1287 |
| work_keys_str_mv | AT undralmunkhsaikhan thebeneficialeffectoflomitapideonthecardiovascularsysteminldlrsupsupmicewithobesity AT younginkwon thebeneficialeffectoflomitapideonthecardiovascularsysteminldlrsupsupmicewithobesity AT amalmsahyoun thebeneficialeffectoflomitapideonthecardiovascularsysteminldlrsupsupmicewithobesity AT mariagalan thebeneficialeffectoflomitapideonthecardiovascularsysteminldlrsupsupmicewithobesity AT alexisagonzalez thebeneficialeffectoflomitapideonthecardiovascularsysteminldlrsupsupmicewithobesity AT karimaaitaissa thebeneficialeffectoflomitapideonthecardiovascularsysteminldlrsupsupmicewithobesity AT ammaarhabidi thebeneficialeffectoflomitapideonthecardiovascularsysteminldlrsupsupmicewithobesity AT adamkassan thebeneficialeffectoflomitapideonthecardiovascularsysteminldlrsupsupmicewithobesity AT modarkassan thebeneficialeffectoflomitapideonthecardiovascularsysteminldlrsupsupmicewithobesity AT undralmunkhsaikhan beneficialeffectoflomitapideonthecardiovascularsysteminldlrsupsupmicewithobesity AT younginkwon beneficialeffectoflomitapideonthecardiovascularsysteminldlrsupsupmicewithobesity AT amalmsahyoun beneficialeffectoflomitapideonthecardiovascularsysteminldlrsupsupmicewithobesity AT mariagalan beneficialeffectoflomitapideonthecardiovascularsysteminldlrsupsupmicewithobesity AT alexisagonzalez beneficialeffectoflomitapideonthecardiovascularsysteminldlrsupsupmicewithobesity AT karimaaitaissa beneficialeffectoflomitapideonthecardiovascularsysteminldlrsupsupmicewithobesity AT ammaarhabidi beneficialeffectoflomitapideonthecardiovascularsysteminldlrsupsupmicewithobesity AT adamkassan beneficialeffectoflomitapideonthecardiovascularsysteminldlrsupsupmicewithobesity AT modarkassan beneficialeffectoflomitapideonthecardiovascularsysteminldlrsupsupmicewithobesity |