van Ingen Eva, Foks Amanda C, Kröner Mara J, Kuiper Johan, Quax Paul H A, Bot Ilze, Nossent Anne Yaël
Department of Surgery, Leiden University Medical Center, 2300 RC, Leiden, the Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, 2300 RC, Leiden, the Netherlands.
Division BioTherapeutics, LACDR, Leiden University, 2333 CC, Leiden, the Netherlands.
Mol Ther Nucleic Acids. 2019 Dec 6;18:638-649. doi: 10.1016/j.omtn.2019.09.021. Epub 2019 Sep 30.
We have previously shown that third-generation antisense (3GA) inhibition of 14q32 microRNA (miRNA)-494 reduced early development of atherosclerosis. However, patients at risk of atherosclerotic complications generally present with advanced and unstable lesions. Here, we administered 3GAs against 14q32 miRNA-494 (3GA-494), miRNA-329 (3GA-329), or a control (3GA-ctrl) to mice with advanced atherosclerosis. Atherosclerotic plaque formation in LDLr mice was induced by a 10-week high-fat diet and simultaneous carotid artery collar placement. Parallel to 3GA-treatment, hyperlipidemia was normalized by a diet switch to regular chow for an additional 5 weeks. We show that, even though plasma cholesterol levels were normalized after diet switch, carotid artery plaque progression continued in 3GA-ctrl mice. However, treatment with 3GA-494 and, in part, 3GA-329 halted plaque progression. Furthermore, in the aortic root, intra-plaque collagen content was increased in 3GA-494 mice, accompanied by a reduction in the intra-plaque macrophage content. Pro-atherogenic cells in the circulation, including inflammatory Ly6C monocytes, neutrophils, and blood platelets, were decreased upon miRNA-329 and miRNA-494 inhibition. Taken together, treatment with 3GA-494, and in part with 3GA-329, halts atherosclerotic plaque progression and promotes stabilization of advanced lesions, which is highly relevant for human atherosclerosis.
我们之前已经表明，对14q32微小RNA（miRNA）-494进行第三代反义（3GA）抑制可减少动脉粥样硬化的早期发展。然而，有动脉粥样硬化并发症风险的患者通常表现为晚期和不稳定病变。在此，我们对患有晚期动脉粥样硬化的小鼠给予针对14q32 miRNA-494（3GA-494）、miRNA-329（3GA-329）或对照（3GA-ctrl）的3GA。通过10周高脂饮食和同时放置颈动脉套环诱导LDLr小鼠形成动脉粥样硬化斑块。与3GA治疗同时，通过将饮食换成普通饲料再持续5周使高脂血症恢复正常。我们发现，尽管饮食转换后血浆胆固醇水平恢复正常，但3GA-ctrl小鼠的颈动脉斑块仍继续进展。然而，3GA-494以及部分3GA-329治疗可阻止斑块进展。此外，在主动脉根部，3GA-494小鼠斑块内的胶原蛋白含量增加，同时斑块内巨噬细胞含量减少。在miRNA-329和miRNA-494受到抑制后，循环中的促动脉粥样硬化细胞，包括炎性Ly6C单核细胞、中性粒细胞和血小板减少。综上所述，3GA-494以及部分3GA-329治疗可阻止动脉粥样硬化斑块进展并促进晚期病变的稳定，这与人类动脉粥样硬化高度相关。
