MicroRNA-144 Silencing Protects Against Atherosclerosis in Male, but Not Female Mice
Autor: | Xiaohui Wu, Angela Cheng, Thomas Q. de Aguiar Vallim, Elizabeth J. Tarling, Joan Cheng, Lars Maegdefessel, Ulf Hedin, Bethan L. Clifford, Nathalie Pamir, Tamer Sallam |
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Rok vydání: | 2020 |
Předmět: |
Male
Mice Knockout Blotting Western Biology Atherosclerosis Article Pathophysiology Disease Models Animal Mice MicroRNAs Cholesterol Sex Factors Gene expression microRNA Antisense oligonucleotides Cancer research Animals RNA Gene silencing Female lipids (amino acids peptides and proteins) Gene Silencing Cardiology and Cardiovascular Medicine Cause of death |
Zdroj: | Arterioscler Thromb Vasc Biol |
ISSN: | 1524-4636 1079-5642 |
Popis: | Objective: Atherosclerosis is a leading cause of death in developed countries. MicroRNAs act as fine-tuners of gene expression and have been shown to have important roles in the pathophysiology and progression of atherosclerosis. We, and others, previously demonstrated that microRNA-144 (miR-144) functions to post-transcriptionally regulate ABCA1 (ATP binding cassette transporter A1) and plasma HDL (high-density lipoprotein) cholesterol levels. Here, we explore how miR-144 inhibition may protect against atherosclerosis. Approach and Results: We demonstrate that miR-144 silencing reduced atherosclerosis in male, but not female low-density lipoprotein receptor null ( Ldlr −/− ) mice. MiR-144 antagonism increased circulating HDL cholesterol levels, remodeled the HDL particle, and enhanced reverse cholesterol transport. Notably, the effects on HDL and reverse cholesterol transport were more pronounced in male mice suggesting sex-specific differences may contribute to the effects of silencing miR-144 on atherosclerosis. As a molecular mechanism, we identify the oxysterol metabolizing enzyme CYP7B1 (cytochrome P450 enzyme 7B1) as a miR-144 regulated gene in male, but not female mice. Consistent with miR-144-dependent changes in CYP7B1 activity, we show decreased levels of 27-hydroxycholesterol, a known proatherogenic sterol and the endogenous substrate for CYP7B1 in male, but not female mice. Conclusions: Our data demonstrate silencing miR-144 has sex-specific effects and that treatment with antisense oligonucleotides to target miR-144 might result in enhancements in reverse cholesterol transport and oxysterol metabolism in patients with cardiovascular disease. |
Databáze: | OpenAIRE |
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