TY - JOUR
T1 - Induction of MiR133a expression by IL-19 targets LDLRAP1 and reduces oxLDL uptake in VSMC
AU - Gabunia, Khatuna
AU - Herman, Allison B.
AU - Ray, Mitali
AU - Kelemen, Sheri E.
AU - England, Ross N.
AU - Cadena, Raul De La
AU - Foster, William J.
AU - Elliott, Katherine J.
AU - Eguchi, Satoru
AU - Autieri, Michael V.
N1 - Publisher Copyright:
© 2017 Elsevier Ltd
PY - 2017/4/1
Y1 - 2017/4/1
N2 - 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.
AB - 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.
KW - Adaptor Proteins, Signal Transducing/genetics
KW - Animals
KW - Cell Line
KW - Cell Proliferation
KW - Cells, Cultured
KW - Cholesterol/metabolism
KW - Endothelial Cells/metabolism
KW - Gene Expression Regulation
KW - Humans
KW - Hyperlipidemias/genetics
KW - Interleukins/metabolism
KW - Lipoproteins, LDL/metabolism
KW - Mice
KW - MicroRNAs/genetics
KW - Myocytes, Smooth Muscle/metabolism
KW - RNA Interference
KW - RNA, Messenger/genetics
UR - http://www.scopus.com/inward/record.url?scp=85014229388&partnerID=8YFLogxK
UR - https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=purepublist2023&SrcAuth=WosAPI&KeyUT=WOS:000399516800004&DestLinkType=FullRecord&DestApp=WOS
U2 - 10.1016/j.yjmcc.2017.02.005
DO - 10.1016/j.yjmcc.2017.02.005
M3 - Article
C2 - 28257760
SN - 0022-2828
VL - 105
SP - 38
EP - 48
JO - Journal of Molecular and Cellular Cardiology
JF - Journal of Molecular and Cellular Cardiology
ER -