1. Induction of MiR133a expression by IL-19 targets LDLRAP1 and reduces oxLDL uptake in VSMC
- Author
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Katherine J. Elliott, Michael V. Autieri, Raul A. DeLa Cadena, William J. Foster, Satoru Eguchi, Khatuna Gabunia, Mitali Ray, Sheri E. Kelemen, Allison B. Herman, and Ross N. England
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Vascular smooth muscle ,medicine.medical_treatment ,Myocytes, Smooth Muscle ,Hyperlipidemias ,Inflammation ,Biology ,Article ,Cell Line ,Mice ,03 medical and health sciences ,Internal medicine ,medicine ,Animals ,Humans ,RNA, Messenger ,Molecular Biology ,Cells, Cultured ,Adaptor Proteins, Signal Transducing ,Cell Proliferation ,Regulation of gene expression ,Interleukins ,Endothelial Cells ,Signal transducing adaptor protein ,Lipid metabolism ,Transfection ,Cell biology ,Lipoproteins, LDL ,MicroRNAs ,Cholesterol ,030104 developmental biology ,Cytokine ,Endocrinology ,Gene Expression Regulation ,LDL receptor ,RNA Interference ,medicine.symptom ,Cardiology and Cardiovascular Medicine - Abstract
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.
- Published
- 2017