miR33 Inhibition Overcomes Deleterious Effects of Diabetes Mellitus on Atherosclerosis Plaque Regression in Mice

Abstract

Rationale Diabetes increases cardiovascular disease risk in humans and remains elevated despite cholesterol-lowering therapy with statins. Consistent with this, in mouse models diabetes impairs atherosclerosis plaque regression after aggressive cholesterol-lowering. miR33 is a key negative regulator of the reverse cholesterol transport factors, ABCA1 and HDL, which suggested that its inhibition may overcome this impairment. Objective To assess the effects of miR33 inhibition on atherosclerosis regression in diabetic mice. Methods and Results Reversa mice, which are deficient in the LDL receptor and in which hypercholesterolemia is reversed by conditional inactivation of the microsomal triglyceride transfer protein (Mttp) gene, were placed on an atherogenic diet for 16 weeks, then either made diabetic by STZ injection or kept normoglycemic. Lipid-lowering was induced by Mttp inactivation and mice were treated with anti-miR33 or control oligonucleotides. Whereas regression was impaired in diabetic mice treated with control oligonucleotides, anti-miR33 treatment decreased plaque macrophage content and inflammatory gene expression in these mice. The decreased macrophage content in anti-miR33-treated diabetic mice was associated with a blunting of hyperglycemia-induced monocytosis and reduced monocyte recruitment to the plaque, which was traced to an inhibition of the proliferation of bone marrow monocyte precursors associated with the upregulation of their Abca1. Conclusions miR33 inhibition overcomes deleterious effects of diabetes in atherosclerosis regression in mice, which suggests a therapeutic strategy in diabetic patients, who remain at elevated cardiovascular disease risk despite plasma cholesterol lowering.

MicroRNA-mediated mechanisms of the cellular stress response in atherosclerosis

“…Suppression of Abca1 mRNA by miR-33-5p in mice also inhibits the proliferation of monocyte precursor cells in the bone marrow and promotes lesional macrophage accumulation during regression of atherosclerosis in diabetic mice (Table 1). 175 Hyperlipidaemia-induced downregulation of miR-33-5p in macrophages derepresses receptorinteracting protein 140 (RIP140; also known as nuclear receptor-interacting protein 1, NRIP1). 176 RIP140 functionally links the metabolic and inflammatory pathways through its role as a corepressor or coactivator of numerous nuclear receptors, such as LXR, retinoid X receptor, and PPARs, and is a coactivator of NF-κB-dependent genes.…”

RAGE Against the ABCs

“…Another point of interest would be to determine the type of macrophages within the atherosclerotic lesion in the current study, as previous reports have shown a major skewing toward the M1-inflammatory phenotype in the setting of diabetes (3)(4)(5). Treating diabetic mice with the ABC-inducing anti-miR-33 (20) does suggest that restoring the expression of these genes equates to less M1-and more M2-like macrophages ( Fig.…”

“…This can be achieved by cholesterol-lowering drugs (i.e., statins) or by enhancing the reverse cholesterol transport pathway (i.e., raising HDL). Unfortunately, in the setting of diabetes, cholesterol-lowering drugs such as statins can be less effective (2), and preclinical models have revealed a major defect in lesion regression even when cholesterol levels are normalized (3)(4)(5). This suggests that a major defect in cholesterol metabolism occurs in the setting of diabetes.…”

Gene-based therapies in lipidology

“…For instance, a set of miRNAs, which includes miR-33, controls the expression of most of the genes associated with HDL metabolism, including ATP transporters, ABCA1 and ABCG1, and scavenger receptor SRB1, thereby controlling several steps of reverse cholesterol transport [31,32]. It has been shown that miR-33 inhibition promotes regression and reduces progression of atherosclerosis [33].…”