MicroRNA-144 Silencing Protects Against Atherosclerosis in Male, but Not Female Mice

Abstract

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.

The Role of the ATP-Binding Cassette A1 (ABCA1) in Human Disease

“…In addition, studies in tissue-specific FXR deficient mice showed that hepatic but not intestinal FXR is essential for induction of miR-144 and FXR-dependent hypolipidemia. Interestingly, miR-144 was found to have sex-specific silencing effects [ 55 ]. Finally, miR-148a was found to control in vivo hepatic ABCA1 expression and circulating HDL-C levels, revealing a role for miR-148a as a key regulator of hepatic LDL-C clearance through direct modulation of LDLR expression, and showing the therapeutic potential of miR-148a inhibition to improve the elevated LDL-C/HDL-C ratio, a significant risk factor for cardiovascular disease [ 56 ].…”

Genetics of macrovascular complications in type 2 diabetes

“…A study by Chen et al [ 103 ] concluded that increased plasma level of miR-144 might serve as a promising biomarker for CAD and its severity. This association can be partially explained by the recent research that demonstrated the involvement of miR-144 in cholesterol and oxysterol metabolism in male CAD mice[ 104 ]. Moreover, altered expression of miR-144 was shown to be a risk factor for ischemic stroke in T2DM patients[ 98 ].…”

Potential role of anti-inflammatory HDL subclasses in metabolic unhealth/obesity

“…The picture of HDL-C as the "good" cholesterol has eroded. Previous also have indicated that epigenetic changes within the ABCA1 (ATP-binding cassette A1) gene promoter among French-Canadian founder population contribute to the interindividual variability in plasma HDL-C concentrations and are associated with coronary artery disease (CAD) expression with negatively related to HDL-2 phospholipid level and HDL particle size [7], while MicroRNA-144 antagonism in male mice increase circulating HDL cholesterol levels by remodeling the HDL particle, and enhance reverse cholesterol transport through performing an effect with 3 0 -UTR harbours binding sites for miR-33, miR-758, and miR-26 of Cyp7b1 which have been shown to regulate Abca1 and lipid metabolism [8].…”