miR-33a/miR-33b and Atherosclerosis

In response to these initial findings, numerous studies have been performed assessing the impact of miR-33 antagonism on atherosclerosis in mice. The first study of this sort demonstrated that short-term (4-week) administration of miR-33 inhibitors to Ldlr~'~ mice with established plaques was capable of raising HDL-C levels and promoting atherosclerotic plaque regression (Rayner et al. 2011b). However, another study found that treatment with anti-miR-33 ASOs did not sustain elevated plasma HDL-C levels during a 12-week atherosclerosis progression study, raised plasma triglycerides, and did not have any effect on plaque development (Marquart et al. 2013). Three additional atherosclerosis progression studies using Ldlr~'~ (Rotllan et al. 2013; Ouimet et al. 2015) and ApoE~'~ mice (Karunakaran et al. 2015b) reported a decrease in plaque burden in animals treated with miR-33 inhibitors. Surprisingly, although the expression of ABCA1 in the liver and/or macrophages was elevated in mice treated with miR-33 ASOs, HDL-C remained unchanged in these progression studies (Rotllan et al. 2013; Ouimet et al. 2015; Karunakaran et al. 2015b). Together, these findings suggest that the antiatherosclerotic effects of the ASOs may be the result of direct effects on the plaque rather than alterations in circulating lipids. Consistent with this theory, anti-miR-33 ASOs were found to be efficiently taken up by macrophages in the aortic root of Ldlr~'~ mice, which could promote ABCA1-/ABCG1-mediated cholesterol efflux. Additionally, it has been reported that anti-miR-33 ASOs decreased inflammatory burden and promoted the recruitment of M2-like macrophages (Rayner et al. 2011b; Ouimet et al. 2015) and Treg cells (Ouimet et al. 2015). Furthermore, bone marrow transplant experiments in which ApoE~'~ mice were reconstituted with ApoE~'~ x miR-33~'~ bone marrow demonstrated that loss of miR-33 in hematopoietic cells caused reduced lipid accumulation in atherosclerotic plaques but did not affect HDL-C levels or total plaque size (Horie et al. 2012). However, whole-body loss of miR-33 in ApoE~'~ mice did increase plasma HDL-C and reduce total plaque size (Horie et al. 2012). While the low levels of HDL-C and impaired macrophage cholesterol efflux of ApoE-~ mice make this a poor model in which to study effects on reverse cholesterol transport, these findings do indicate that both the liver and macrophages are likely involved in mediating the effects of miR-33 on atherosclerotic plaque formation, although the specific contributions are still not entirely clear.

In addition to its role in regulating lipid metabolism, further studies have showed that miR-33 can also target a number of genes involved in other metabolic processes including fatty acid p-oxidation, insulin signaling, and mitochondrial function (Karunakaran et al. 2015b; Gerin et al. 2010; Davalos et al. 2011; Ramirez et al. 2013a). These findings highlight the complex role of miR-33 in regulating metabolic function and indicate that it may have more diverse functions than have previously been elucidated. Consistent with this, miR-33~'~ mice on a high-fat diet were found to gain more weight than control animals, leading to more rapid development of hepatic steatosis and insulin resistance (Horie et al. 2013). Similarly, some studies have indicated that prolonged anti-miR-33 therapy may cause unwanted effects such as hypertriglyceridemia (Marquart et al. 2013; Allen et al. 2014; Goedeke et al. 2014) and hepatic steatosis (Goedeke et al. 2014). In contrast, similar long-term miR-33 inhibitor studies showed no change (Rotllan et al. 2013; Ouimet et al. 2015; Horie et al. 2012; Rottiers et al. 2013) or even a decrease (Karunakaran et al. 2015a; Rayner et al. 2011a) in plasma triacylglycerides (TAGs) in mice and nonhuman primates.

Overall, these studies indicate that anti-miR-33 therapies may be a promising approach for developing novel therapies for atheroprotection. However, the multitude of miR-33 targets involved in many different metabolic functions, and the potential for adverse effects of long-term miR-33 inhibition warrant further exploration. Additionally, because there are two isoforms of miR-33 present in humans, but mice and other rodents do not express miR-33b, little is known about the role of this miRNA in regulating atherosclerotic plaque development and overall metabolic function. This is especially important because the host genes for miR-33a and miR- 33b (SREBP2 and SREBP1) are regulated by different nutritional and hormonal stimuli and miR-33b is more likely to be altered under conditions of metabolic dysfunction such as diabetes and obesity. Recently, a miR-33b knock-in model was reported (Horie et al. 2014), which should allow further exploration of the role of miR-33b in atherosclerosis and other metabolic diseases.

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