Short-Term Acyl-CoA:Cholesterol Acyltransferase Inhibition, Combined with Apoprotein A1 Overexpression, Promotes Atherosclerosis Inflammation Resolution in Mice

Amengual, Jaume; Ogando, Yoscar; Nikain, Cyrus; Quezada, Alexandra; Qian, Kun; Vaisar, Tomáš; Fisher, Edward A.

doi:10.1124/molpharm.120.000108

Cited by 12 publications

(6 citation statements)

References 54 publications

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“…To validate the results obtained in our ASO-LDLR reversible model of atherosclerosis, we utilized Ldlr -/- mice fed WD-VAD subjected to a dietary switch strategy to lower cholesterol in plasma and promote atherosclerosis resolution [18, 30]. Baseline Ldlr -/- mice were harvested after 12 weeks on WD-VAD, while the remaining animals were switched to either a Standard diet without vitamin A (Resolution – Control) or the same diet supplemented with β-carotene (Resolution – β-carotene) for four more weeks.…”

Section: Resultsmentioning

confidence: 99%

“…In this study, we tested the effect of dietary β-carotene on atherosclerosis resolution in two independent experimental models. We characterized plaque composition by probing for macrophage and collagen contents, two parameters utilized to characterize atherosclerotic lesions undergoing resolution [18][19][20][21]. Lastly, we utilized Bco1 -/mice and CD25 + Treg depletion experiments in Foxp3 EGFP mice to tease out the direct implications of vitamin A formation and Tregs on atherosclerosis resolution.…”

Section: Introductionmentioning

confidence: 99%

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β-carotene accelerates the resolution of atherosclerosis in mice

Pinos

Coronel

Albakri

et al. 2023

Preprint

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β-carotene oxygenase 1 (BCO1) catalyzes the cleavage of β-carotene to form vitamin A. Besides its role in vision, vitamin A regulates the expression of genes involved in lipid metabolism and immune cell differentiation. BCO1 activity is associated with the reduction of plasma cholesterol in humans and mice, while dietary β-carotene reduces hepatic lipid secretion and delays atherosclerosis progression in various experimental models. Here we show that β-carotene also accelerates atherosclerosis resolution in two independent murine models, independently of changes in body weight gain or plasma lipid profile. Experiments inBco1-/-mice implicate vitamin A production in the effects of β-carotene on atherosclerosis resolution. To explore the direct implication of dietary β-carotene on regulatory T cells (Tregs) differentiation, we utilized anti-CD25 monoclonal antibody infusions. Our data show that β-carotene favors Treg expansion in the plaque, and that the partial inhibition of Tregs mitigates the effect of β-carotene on atherosclerosis resolution. Our data highlight the potential of β-carotene and BCO1 activity in the resolution of atherosclerotic cardiovascular disease.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

β-carotene accelerates the resolution of atherosclerosis in mice

Pinos

Coronel

Albakri

et al. 2023

Preprint

Self Cite

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“…These results were extended to pre-existing lesions, where the mice treated with an ACAT inhibitor had slower lesion progression, with less macrophage, FC, and CE accumulation [35]. After switching Apoe −/− mice from a Western-type diet to a chow diet, the short-term addition of F-1394 decreased the lesion macrophage pro-inflammatory gene expression and increased the inflammation resolving gene expression [36]. Pactimibe sulfate (CS-505) treatment of Apoe −/− mice fed a chow diet decreased plasma cholesterol along with aortic root lesion development and progression, with the lesions being more significantly reduced with pactimibe sulfate vs. avasimibe treatment, despite similar effects on plasma cholesterol [43].…”

mentioning

confidence: 82%

Acyl-Coenzyme A: Cholesterol Acyltransferase (ACAT) in Cholesterol Metabolism: From Its Discovery to Clinical Trials and the Genomics Era

Hai

Smith

2021

Metabolites

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The purification and cloning of the acyl-coenzyme A: cholesterol acyltransferase (ACAT) enzymes and the sterol O-acyltransferase (SOAT) genes has opened new areas of interest in cholesterol metabolism given their profound effects on foam cell biology and intestinal lipid absorption. The generation of mouse models deficient in Soat1 or Soat2 confirmed the importance of their gene products on cholesterol esterification and lipoprotein physiology. Although these studies supported clinical trials which used non-selective ACAT inhibitors, these trials did not report benefits, and one showed an increased risk. Early genetic studies have implicated common variants in both genes with human traits, including lipoprotein levels, coronary artery disease, and Alzheimer’s disease; however, modern genome-wide association studies have not replicated these associations. In contrast, the common SOAT1 variants are most reproducibly associated with testosterone levels.

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“…TC and TG need to combine with apolipoproteins for transportation. 42 Lipoproteins play a direct role in lipid transport and clearance in the blood. 43 Apo-A1 is an HDL apolipoprotein that can esterify free TC, minimize cholesterol buildup in cells, and improve clearance of atherosclerotic plaque cholesterol.…”

Section: Papermentioning

confidence: 99%