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.

Objective In this study, the effect of lomitapide, a microsomal triglyceride transfer protein inhibitor, on the cardiovascular function in obesity was investigated. Methods Eight‐week‐old C57BL/6 mice were fed with high‐fat diet for 12 weeks in the presence and absence of lomitapide. Lomitapide was administered by gavage (1 mg/kg/d) during the last 2 weeks of high‐fat feeding. Body weight, blood glucose, body composition, and lipid profile were determined. Vascular function and endothelial function markers were studied in the aorta and mesenteric resistance arteries. Results Lomitapide treatment reduced body weight in mice with obesity. Blood glucose, percentage of fat mass, total cholesterol, and low‐density lipoprotein levels were significantly reduced, and the percentage of lean mass was significantly increased after lomitapide treatment. The vascular response to sodium nitroprusside in the aorta and mesenteric arteries was similar among groups. However, the vascular response to acetylcholine was improved in the treated group. This was associated with decreased levels of vascular endoplasmic reticulum stress, inflammation, and oxidative stress. Conclusions Treatment with lomitapide attenuated the increase in body weight in mice with obesity and restored the lipid profile and vascular function. These effects were accompanied by a decrease in inflammation and oxidative stress.

Hypertension, which is associated with gut dysbiosis, is an independent and preventable risk factor for the development of cardiovascular diseases. The gut microbiota and its metabolites such as short‐chain fatty acids (SCFAs) play an important role in host physiology. SCFAs can regulate blood pressure in both rodent models and humans. However, the exact mechanism by which SCFA regulates hypertension is unknown. Our data showed that SCFAs can regulate miR‐204, a non‐coding RNA that is expressed in vessels. We recently showed that miR‐204, is reduced in vessels during hypertension. Additionally, miR‐204 targets inositol 1, 4, 5‐triphosphate receptor type1 (IP3R1) and therefore disrupt the calcium release into the cytosol leading to exacerbated vascular constriction. Thus, we hypothesize that SCFAs can regulate blood pressure and vascular constriction through miRNA‐204/IP3R1/Ca2+ axis. To test our hypothesis, we treated hypertensive mice with SCFAs cocktail (67.5 mM acetate, 40 mM butyrate, 25.9 mM propionate) in drinking water for 21 days. Increased blood pressure from hypertensive mice was reduced after SCFAs intake. Aortas and mesenteric arteries from hypertensive mice display increased vasoconstriction in response to phenylephrine, U46619, and angiotensin II. Treatment with SCFAs reduced vasoconstriction in response to all agonists. During hypertension, aortas display low levels of miR‐204 expression which was recovered after SCFAs intake. Additionally, IP3R1 was significantly up‐regulated in hypertensive mice and decreased after SCFAs supplementation. Furthermore, our in vitro data showed that SCFAs can directly affect the vascular miRNA‐204/IP3R1/Ca2+ axis. Our results suggest that SCFAs can regulate Ca2+ homeostasis and vascular contraction through the miR‐204/IP3R1 axis. The outcome of this study will establish novel treatment strategies conferring the benefits of SCFA control while circumventing the potential risks of delivering live biologics.

Objectives Bacteria dysbiosis is very well documented in obesity and is known to regulate the cardiovascular system. Recovering the bacteria composition is a key element in improving the cardiovascular function during obesity. Hypothesis In this study we investigate the effect of levan, a novel second generation of prebiotic (β‐[2,6]‐linkages, on the cardiovascular system in obesity. Methods Eight‐week‐old C57/b6 mice were fed with high fat diet (HFD) for 12 weeks in the presence and absence of levan (β‐[2,6]‐linkages). Treatment was administered by gavage (250 mg/kg) for the last 30 days of HFD feeding. Body weight, 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 Levan (β‐[2,6]‐linkages) 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 Levan (β‐[2,6]‐linkages) 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. Conclusions Treatment with Levan (β‐[2,6]‐linkages) attenuated the increase in body weight in obese mice and restored the lipid profile and the vascular function.