The Microsomal Triglyceride Transfer Protein Inhibitor, Lomitapide, Improves Vascular Function in Obesity

Abstract

Objectives In this study, we investigate the effect of lomitapide, a microsomal triglyceride transfer protein inhibitor, on cardiovascular function in obesity. Hypothesis We hypothesize that lipid level downregulation by lomitapide is a fundamental mechanism that improves cardiovascular function. Methods Eight‐week‐old C57/b6 mice were fed with a high fat diet (HFD) for 12 weeks in the presence and absence of lomitapide. Lomitapide was administered by gavage (1mg/Kg/Day) for the last 2 weeks of HFD feeding. Bodyweight, blood glucose, body composition, and lipid profile were determined. Vascular function and endothelial function markers were studied in aorta and mesenteric resistance arteries (MRA). Results Lomitapide treatment reduced the body weight in obese mice. Blood glucose, % of fat mass, total cholesterol, and LDL levels were significantly reduced and the % of lean mass was significantly increased after lomitapide treatment. Aortic and mesenteric arteries vascular response to sodium nitroprusside (SNP) was similar among groups. However, the vascular response to acetylcholine (Ach) was improved in the treated group. This was associated with a decreased level of vascular endoplasmic (ER) reticulum stress, inflammation, and oxidative stress. Conclusions Treatment with lomitapide attenuated the increase in body weight in obese mice and restored the lipid profile and vascular function. These effects were accompanied by a decrease in inflammation and oxidative stress.

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

“…Blood samples were taken by cardiac puncture, then plasma was separated by centrifugation (2000× g , 15 min, 4 °C) and stored at −80 °C until further use [ 37 ]. As previously described [ 34 ], the lipid profile was assessed in plasma using the following assays: HDL and LDL/VLDL quantification kit (Sigma, Burlington, MA, USA, MAK045), Triglyceride quantification kit (Sigma, Burlington, MA, USA, MAK266), and Cholesterol quantification kit (Sigma, Burlington, MA, USA, MAK043), according to the manufacturer’s protocol. Arteries, such as mesenteric resistance arteries (MRA) and thoracic aorta, were harvested to determine protein levels by Western blot, gene expression by quantitative real-time (qRT-) PCR, and vascular reactivity using the wire myograph.…”

“…Thoracic aorta and mesenteric resistance arteries (MRA) were used to evaluate the vascular reactivity as previously described [ 34 ]. Briefly, thoracic aorta and MRA were placed in a chilled Krebs solution of the following composition (in mM): NaCl, 118; KCl, 4.7; CaCl 2 , 2.5; KH 2 PO 4 , 1.2; MgSO 4 , 1.2; NaHCO 3 , 25; and glucose, 11.…”

“…Then, suitable primary antibodies were added and followed by secondary antibodies that were conjugated with horseradish peroxidase. Protein expression was determined as previously described [ 34 ]. Primary antibodies used in this study were as follows: markers for nitric oxide enzyme (Cell Signaling, Boston, MA, USA) (total (T) endothelial nitric oxide synthase (eNOS) (9586S, anti-rabbit) and phosphorylated (P) eNOS (9571S, anti-rabbit)), markers for endoplasmic reticulum (ER) stress (BIP (3177S, anti-rabbit) and CHOP (2895S, anti-mouse)), and markers for inflammation (P65 (8242S, anti-rabbit) and TNFα (3707S, anti-rabbit)).…”

“…Mouse thoracic aortas were harvested from all groups to determine gene expression for endoplasmic reticulum (ER) stress markers (BIP, ATF6, and ATF4), oxidative stress markers (NOX2), and inflammatory markers (P65, P50, TNFα, and VCAM-1). Gene expression was determined using real-time quantitative PCR as previously described [ 34 ]. Total RNA was isolated from 50 mg of thoracic aorta using RNeasy Micro Kit (Qiagen, Venlo, The Netherlands) as per the manufacturer’s instruction.…”

“…A recent study found a reduction in inflammatory markers (TNFα, IL-7) in the plasma of patients treated for 6 months, suggesting that lomitapide may have an anti-inflammatory effect [ 33 ]. In our previous study, we showed that lomitapide had beneficial effects on the cardiovascular system of mice with obesity [ 34 ]. However, less is known about the effect of lomitapide on the cardiovascular system in the HoFH mouse model (LDLr − / − mice).…”