Antagonism of miR-33 in mice promotes reverse cholesterol transport and regression of atherosclerosis

Abstract

Plasma HDL levels have a protective role in atherosclerosis, yet clinical therapies to raise HDL levels have remained elusive. Recent advances in the understanding of lipid metabolism have revealed that miR-33, an intronic microRNA located within the SREBF2 gene, suppresses expression of the cholesterol transporter ABC transporter A1 (ABCA1) and lowers HDL levels. Conversely, mechanisms that inhibit miR-33 increase ABCA1 and circulating HDL levels, suggesting that antagonism of miR-33 may be atheroprotective. As the regression of atherosclerosis is clinically desirable, we assessed the impact of miR-33 inhibition in mice deficient for the LDL receptor (Ldlr -/-mice), with established atherosclerotic plaques. Mice treated with anti-miR33 for 4 weeks showed an increase in circulating HDL levels and enhanced reverse cholesterol transport to the plasma, liver, and feces. Consistent with this, anti-miR33-treated mice showed reductions in plaque size and lipid content, increased markers of plaque stability, and decreased inflammatory gene expression. Notably, in addition to raising ABCA1 levels in the liver, anti-miR33 oligonucleotides directly targeted the plaque macrophages, in which they enhanced ABCA1 expression and cholesterol removal. These studies establish that raising HDL levels by anti-miR33 oligonucleotide treatment promotes reverse cholesterol transport and atherosclerosis regression and suggest that it may be a promising strategy to treat atherosclerotic vascular disease.

Hepatic ABCA1 Expression Improves β-Cell Function and Glucose Tolerance

“…ABCA1 is considered an important target for the development of such HDL-increasing strategies. Increased ABCA1 concentrations due to treatment with liver X receptor agonists or microRNA-33 inhibitors have been shown to increase plasma HDL-cholesterol concentrations in mice and monkeys, and these interventions reduce atherosclerosis in hyperlipidemic mice (23)(24)(25). Our data suggest that such drugs may also be beneficial and improve b-cell function in diabetes.…”

“…HDL-increasing therapies for the treatment of patients with dyslipidemia are currently under development (23)(24)(25). ABCA1 is considered an important target for the development of such HDL-increasing strategies.…”

MicroRNA and Its Role in Cardiovascular Disease

“…Atheroprotective effect of miR-126 has been explained by [69]. Similarly anti miR-33 therapy has found to be atheroprotective by increasing circulating HDL in mice model [70] (Table 1).…”

“…Similarly anti miR-33 therapy has found to be atheroprotective by increasing circulating HDL in mice model [70]. A study done by Gao et al [71] in 355 Chinese patients with hyperlipidemia found that level of miR-122 and miR-370 were positively correlated with total cholesterol, Triglycerides and Low density lipoprotein cholesterol C (LDL-C) and coronary artery disease (CAD) progression.…”

Strategies to deliver microRNAs as potential therapeutics in the treatment of cardiovascular pathology

“…At present, Miragen Therapeutics develops three (Rayner et al, 2011a(Rayner et al, , 2011b. Hopefully, clinical testing of chemically modified oligonucleotide inhibitors of atherogenic miRNAs is not far to start soon.…”