Atherosclerosis is a chronic arterial disease in which complex mechanisms contribute to lesion initiation and development [1]. Many biochemical and cellular mechanisms have been invoked to describe the evolution of this pathology. There has been a recent focus on diverse roles of microRNAs (miRs) as drivers of the molecular basis of atherosclerotic lesion formation. miRs are a class of small noncoding RNAs (approximately 22 nucleotides) that regulate many physiological and pathophysiological functions through repression of protein translation or promoting mRNA instability. This commentary is a summary of recent selected publications that have provided an insight into roles of miRs in atherosclerosis. Dysfunction in cholesterol metabolism remains a core mechanism of atherosclerotic formation. To gain an insight into a link of cholesterol metabolism and miRs, Rayner et al.[2] manipulated macrophage sterol content and performed an unbiased genomewide screen of miRs. Several candidates were identified including miR-33 that is encoded within intron 16 of sterol regulatory element-binding protein 2 (SREBF2), a transcriptional factor that modulates cholesterol homeostasis. miR-33 expression decreased plasma HDL-cholesterol concentrations in mice through suppressing two cellular sterol transporters, ABCA1 and ABCG1. The authors’ subsequent study demonstrated that miR-33 inhibition influenced atherosclerosis. This was determined in low-density lipoprotein receptor À/À (LdlrÀ/À) mice fed a saturated fat-enriched diet for 14 weeks to promote formation of lesions [3 &&]. Simultaneously with switching to a normal laboratory diet, one group was subcutaneously injected with miR-33 antisense oligonucleotides and compared to groups injected with either vehicle or control miRs. Lesion size in aortic roots of mice administered miR-33 antisense oligonucleotides were impressively decreased 4 weeks later. Although this reduction was associated with only modest increases in plasma HDL-cholesterol concentrations, miR-33 antisense oligonucleotides promoted large increases in reverse cholesterol transport. In addition to the profoundly decreased atherosclerosis, anti-miR-33 oligonucleotides penetrated atherosclerotic lesions and targeted to macrophages, which led to diminished inflammatory gene expression.

These two studies provide strong evidence that inhibition of miR-33 could be an effective antiatherosclerotic strategy. A potentially confounding factor in extrapolation of these studies to humans is that mice only possess miR-33a, in contrast to the presence of both miR-33a and miR-33b in higher classes of mammals. To address this issue, studies were performed using a nonhuman primate, African green monkeys [4 & &]. Monkeys were injected subcutaneously with an antisense oligonucleotide that equally inhibited both miR-33a and miR-33b for 12 weeks, while being fed a high carbohydrate during the last 8 weeks. As in mice, inhibition of both miR-33s resulted in increased plasma HDL-cholesterol concentrations [2, 3 &&, 4 &&]. Further potential benefit was noted in monkeys with miR-33 inhibition promoting significant reductions of plasma triglyceride concentrations attributed to decreases in VLDL-triglyceride concentrations. The intriguing data regarding the effects of miR-33a and miR-33b in cholesterol metabolism and other metabolic disorders have been reviewed recently [5]. In aggregate, these preclinical findings provide insights that inhibition of miR-33 is a promising therapeutic strategy for atherosclerosis in humans.