Induction of MiR133a expression by IL-19 targets LDLRAP1 and reduces oxLDL uptake in VSMC. (April 2017)

• Record Type: Journal Article
• Authors: Gabunia, Khatuna; Herman, Allison B.; Ray, Mitali; Kelemen, Sheri E.; England, Ross N.; DeLa Cadena, Raul; Foster, William J.; Elliott, Katherine J.; Eguchi, Satoru; Autieri, Michael V.
• Is Part Of: Journal of molecular and cellular cardiology. Volume 105(2017)
• Page Start: 38
• Page End: 48
• Publication Date: 2017-04
• Subjects: Vascular smooth muscle cell -- miR133a -- LDLRAP1 -- Cholesterol uptake; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2017.02.005
• Languages: English
• ISSNs: 0022-2828

Abstract

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. Highlights: IL-19 induces miR133a expression in VSMC. miR133a targets LDLRAP1 which regulates LDLR internalization. miR133a and LDLRAP1 siRNA reduce VSMC foam cell formation. IL-19 driven miR133a expression links lipid metabolism and anti-inflammation.