Munkhsaikhan Undral, Kwon Young In, Sahyoun Amal M, Galán María, Gonzalez Alexis A, Ait-Aissa Karima, Abidi Ammaar H, Kassan Adam, Kassan Modar
Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Department of Bioscience Research and General Dentistry, College of Dentistry, The University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Antioxidants (Basel). 2023 Jun 16;12(6):1287. doi: 10.3390/antiox12061287.
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/).
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.
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.
Treatment with lomitapide improves cardiovascular function and lipid profile and reduces body weight and inflammatory markers in LDLr/ mice on HFD.
纯合子家族性高胆固醇血症（HoFH）是一种罕见的、危及生命的代谢性疾病，主要由低密度脂蛋白受体（LDL受体）突变引起。若不治疗，HoFH会导致急性冠状动脉综合征引发过早死亡。洛美他派已获美国食品药品监督管理局（FDA）批准，用于治疗成年HoFH患者以降低血脂水平。然而，洛美他派在HoFH模型中的有益作用仍有待明确。在本研究中，我们使用低密度脂蛋白受体基因敲除小鼠（LDLr - / -）研究了洛美他派对心血管功能的影响。
六周龄的LDLr - / -小鼠喂食标准饮食（SD）或高脂饮食（HFD）12周。在HFD组的最后2周，通过口服灌胃给予洛美他派（1毫克/千克/天）。测量体重和身体组成、血脂谱、血糖和动脉粥样硬化斑块。在传导动脉（胸主动脉）和阻力动脉（肠系膜阻力动脉（MRA））中测定血管反应性和内皮功能标志物。使用中尺度发现V-Plex检测法测量细胞因子水平。
洛美他派治疗后，HFD组的体重（47.5±1.5对40.3±1.8克）、脂肪量百分比（41.6±1.9%对31.8±1.7%）、血糖（215.5±21.9对142.3±7.7毫克/分升）和血脂水平（胆固醇：600.9±23.6对451.7±33.4毫克/分升；LDL/VLDL：250.6±28.9对161.1±12.24毫克/分升；甘油三酯：299.5±24.1对194.1±28.1毫克/分升）显著降低，瘦体重百分比（56.5±1.8%对65.2±2.1%）显著增加。胸主动脉中的动脉粥样硬化斑块面积也减小（7.9±0.5%对5.7±0.1%）。用洛美他派治疗后，HFD喂养的LDLr - / -小鼠组胸主动脉（47.7±6.3%对80.7±3.1%）和肠系膜阻力动脉（66.4±4.3%对79.5±4.6%）的内皮功能得到改善。这与血管内质网（ER）应激、氧化应激和炎症减轻相关。
洛美他派治疗可改善HFD喂养的LDLr - / -小鼠的心血管功能和血脂谱，并降低体重和炎症标志物水平。
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