title: Induction of MiR133a expression by IL-19 targets LDLRAP1 and reduces oxLDL uptake in VSMC.
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.
authors.affiliation: Department of Physiology, Independence Blue Cross Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, United States.
authors.forename: Khatuna
authors.initials: K
authors.lastname: Gabunia
authors.affiliation: Department of Physiology, Independence Blue Cross Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, United States.
authors.forename: Allison B
authors.initials: AB
authors.lastname: Herman
authors.affiliation: Department of Physiology, Independence Blue Cross Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, United States.
authors.forename: Mitali
authors.initials: M
authors.lastname: Ray
authors.affiliation: Department of Physiology, Independence Blue Cross Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, United States.
authors.forename: Sheri E
authors.initials: SE
authors.lastname: Kelemen
authors.affiliation: Department of Physiology, Independence Blue Cross Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, United States.
authors.forename: Ross N
authors.initials: RN
authors.lastname: England
authors.affiliation: Department of Physiology, Independence Blue Cross Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, United States.
authors.forename: Raul
authors.initials: R
authors.lastname: DeLa Cadena
authors.affiliation: Departments of Ophthalmology & Bioengineering, Independence Blue Cross Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, United States.
authors.forename: William J
authors.initials: WJ
authors.lastname: Foster
authors.affiliation: Department of Physiology, Independence Blue Cross Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, United States.
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Elliott
authors.affiliation: Department of Physiology, Independence Blue Cross Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, United States.
authors.forename: Satoru
authors.initials: S
authors.lastname: Eguchi
authors.affiliation: Department of Physiology, Independence Blue Cross Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, United States. Electronic address: mautieri@temple.edu.
authors.forename: Michael V
authors.initials: MV
authors.lastname: Autieri
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D006949:Hyperlipidemias / Q000235:genetics / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000378:metabolism*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C421250:IL19 protein, human; D007378:Interleukins; C469745:LDLRAP1 protein, human; D008077:Lipoproteins, LDL; C548234:MIRN133 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; C099252:oxidized low density lipoprotein; D002784:Cholesterol
keywords: Cholesterol uptake; LDLRAP1; Vascular smooth muscle cell; miR133a