Rotllan Noemi, Price Nathan, Pati Paramita, Goedeke Leigh, Fernández-Hernando Carlos
Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, USA; Integrative Cell Signaling and Neurobiology of Metabolism Program, Section of Comparative Medicine and Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.
Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, USA; Integrative Cell Signaling and Neurobiology of Metabolism Program, Section of Comparative Medicine and Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.
Atherosclerosis. 2016 Mar;246:352-60. doi: 10.1016/j.atherosclerosis.2016.01.025. Epub 2016 Jan 18.
Circulating levels of low-density lipoprotein cholesterol (LDL), and high-density lipoprotein cholesterol (HDL) are two of the most important risk factors for the development of cardiovascular disease (CVD), the leading cause of death worldwide. Recently, miRNAs have emerged as critical regulators of cholesterol metabolism and promising therapeutic targets for the treatment of CVD. A great deal of work has established numerous miRNAs as important regulators of HDL metabolism. This includes miRNAs that target ABCA1, a critical factor for HDL biogenesis and reverse cholesterol transport (RCT), the process through which cells, including arterial macrophages, efflux cellular cholesterol for transport to and removal by the liver. The most well studied of these miRNAs, miR-33, has been demonstrated to target ABCA1, as well as numerous other genes involved in metabolic function and RCT, and therapeutic inhibition of miR-33 was found to increase HDL levels in mice and non-human primates. Moreover, numerous studies have demonstrated the beneficial effects of miR-33 inhibition or knockout on reducing atherosclerotic plaque burden. Even more recent work has identified miRNAs that regulate LDL cholesterol levels, including direct modulation of LDL uptake in the liver through targeting of the LDL receptor. Among these, inhibition of miR-128-1, miR-148a, or miR-185 was found to reduce plasma LDL levels, and inhibition of miR-185 was further demonstrated to reduce atherosclerotic plaque size in ApoE(-/-) mice. Due to their ability to target many different genes, miRNAs have the ability to mediate complex physiologic changes through simultaneous regulation of multiple interrelated pathways. Of particular importance for CVD, inhibition of miR-148a may prove an important therapeutic approach for combating dyslipidemia, as this has been demonstrated to both raise plasma HDL levels and lower LDL levels in mice by targeting both ABCA1 and LDLR, respectively. In this review we highlight recent advances in our understanding of how miRNAs regulate cholesterol metabolism and the development of atherosclerotic plaques and discuss the potential of anti-miRNA therapies for the treatment and prevention of CVD.
低密度脂蛋白胆固醇（LDL）和高密度脂蛋白胆固醇（HDL）的循环水平是心血管疾病（CVD）发生的两个最重要的风险因素，CVD是全球主要的死亡原因。最近，微小RNA（miRNA）已成为胆固醇代谢的关键调节因子和治疗CVD的有前景的治疗靶点。大量研究已确定众多miRNA是HDL代谢的重要调节因子。这包括靶向ABCA1的miRNA，ABCA1是HDL生物合成和逆向胆固醇转运（RCT）的关键因素，RCT是细胞（包括动脉巨噬细胞）将细胞内胆固醇流出并转运至肝脏进行清除的过程。这些miRNA中研究最深入的是miR-33，它已被证明可靶向ABCA1以及许多其他参与代谢功能和RCT的基因，并且发现对miR-33的治疗性抑制可提高小鼠和非人类灵长类动物的HDL水平。此外，众多研究已证明抑制或敲除miR-33对减轻动脉粥样硬化斑块负担具有有益作用。甚至最近的研究还发现了调节LDL胆固醇水平的miRNA，包括通过靶向LDL受体直接调节肝脏中LDL的摄取。其中，抑制miR-128-1、miR-148a或miR-185可降低血浆LDL水平，并且进一步证明抑制miR-185可减小ApoE（-/-）小鼠的动脉粥样硬化斑块大小。由于miRNA能够靶向许多不同的基因，它们有能力通过同时调节多个相互关联的途径来介导复杂的生理变化。对CVD特别重要的是，抑制miR-148a可能是对抗血脂异常的一种重要治疗方法，因为已证明它通过分别靶向ABCA1和LDLR，在小鼠中既能提高血浆HDL水平又能降低LDL水平。在本综述中，我们重点介绍了我们对miRNA如何调节胆固醇代谢和动脉粥样硬化斑块形成的最新认识进展，并讨论了抗miRNA疗法在治疗和预防CVD方面的潜力。
