Induction of MiR133a expression by IL-19 targets LDLRAP1 and reduces oxLDL uptake in VSMC.
Induction of MiR133a expression by IL-19 targets LDLRAP1 and reduces oxLDL uptake in VSMC.
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DOI：
10.1016/j.yjmcc.2017.02.005
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发表时间：
2017-04
影响因子：
5
通讯作者：
Autieri MV
中科院分区：
文献类型：
--
作者：
Gabunia K;Herman AB;Ray M;Kelemen SE;England RN;DeLa Cadena R;Foster WJ;Elliott KJ;Eguchi S;Autieri MV
血管平滑肌细胞(VSMC)转化为泡沫细胞导致斑块大小增加和稳定性降低是动脉粥样硬化形成过程中的关键步骤，但尚未得到充分的研究。我们报道了白介素19(IL-19)是一种新型的抗炎细胞因子，通过对VSMC的抗炎作用减轻动脉粥样硬化。在这项工作中，我们报告了IL-19诱导VSMC中肌肉特异性miRNA miR133a的表达。虽然以前没有报道，但我们报告了miR133a可以靶向并降低低密度脂蛋白受体适配器蛋白1(LDLRAP1)的mRNA丰度、mRNA稳定性和蛋白表达，LDLRAP1是一种作用于低密度脂蛋白受体内化的适配器蛋白。该基因的突变会导致低密度脂蛋白受体功能障碍，并导致人类常染色体隐性高胆固醇血症(ARH)。在这里，我们表明，IL-19通过miR133a依赖的机制减少VSMC中的脂质堆积，以及LDLRAP1的表达和oxLDL的摄取。我们发现LDLRAP1在小鼠和人损伤动脉的斑块和新生内膜VSMC中有表达。将miR133a和LDLRAP1 siRNA导入VSMC，可抑制VSMC增殖和摄取oxLDL。高脂血症患者血浆miR133a水平明显高于正常血脂患者。在IL-19刺激的VSMC中，miR133a的表达代表了先前未知的血管脂代谢与炎症之间的联系，并可能为对抗血管炎症性疾病提供了一个治疗机会。
The transformation of vascular smooth muscle cells [VSMC] into foam cells leading to increased plaque size and decreased stability is a key, yet understudied step in atherogenesis. We reported that Interleukin-19 (IL-19), a novel, anti-inflammatory cytokine, attenuates atherosclerosis by anti-inflammatory effects on VSMC. In this work we report that IL-19 induces expression of miR133a, a muscle-specific miRNA, in VSMC. Although previously unreported, we report that miR133a can target and reduce mRNA abundance, mRNA stability, and protein expression of Low Density Lipoprotein Receptor Adaptor Protein 1, (LDLRAP1), an adaptor protein which functions to internalize the LDL receptor. Mutations in this gene lead to LDL receptor malfunction and cause the Autosomal Recessive Hypercholesterolemia (ARH) disorder in humans. Herein we show that IL-19 reduces lipid accumulation in VSMC, and LDLRAP1 expression and oxLDL uptake in a miR133a-dependent mechanism. We show that LDLRAP1 is expressed in plaque and neointimal VSMC of mouse and human injured arteries. Transfection of miR133a and LDLRAP1 siRNA into VSMC reduces their proliferation and uptake of oxLDL. miR133a is significantly increased in plasma from hyperlipidemic compared with normolipidemic patients. Expression of miR133a in IL-19 stimulated VSMC represents a previously unrecognized link between vascular lipid metabolism and inflammation, and may represent a therapeutic opportunity to combat vascular inflammatory diseases.