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. Our work in the previous funding cycle (HL117724) demonstrated that Interleukin-19 (IL-19), a novel, anti-inflammatory cytokine, attenuates atherosclerosis by multiple anti-inflammatory effects on VSMC as well as by increasing lipid uptake and efflux in macrophage. In published and preliminary studies described here, we show that IL-19 reduces lipid accumulation in VSMC, an atheroprotective event, but without modifying expression of lipid receptors or transporters. IL-19 induces expression of miR133a, a muscle-specific miRNA previously ascribed to regulate VSMC phenotype. Although unrecognized and unreported, we have identified that miR133a can target and reduce expression of Low Density Lipoprotein Receptor Adaptor Protein 1, (LDLRAP1), an adaptor protein which functions to internalize the LDL receptor. Patients with mutations in LDLRAP1 have LDL receptor malfunction leading to hyperlipidemia and Autosomal Recessive Hypercholesterolemia (ARH) disorder. Nothing at all is known about a role for miR133a in regulation of lipid uptake and development of atherosclerosis. Similarly, nothing at all has been published about LDLRAP1 expression, function, and participation in VSMC foam cell formation. We have reported that that both miR133a and LDLRAP1 regulate oxLDL uptake in VSMC. LDLRAP1 is induced in VSMC by oxLDL, is not detectible in normal medial VSMC, but is expressed in plaque and neointimal VSMC of injured arteries. IL-19 can reduce LDLRAP1 expression and oxLDL uptake in VSMC. Both miR133a and LDLRAP1regulate VSMC proliferation, previously unrecognized functions for these molecules. Preliminary studies indicate that the LDLRAP1+/- mouse has increased atherosclerosis, but reduced restenosis. In this competitive renewal application, we hypothesize that LDLRAP1 can be selectively reduced in VSMC because miR133a is muscle specific, and that reduction of lipid uptake by VSMC is atheroprotective and could also attenuate vascular proliferative syndromes. The overall goals of this application are to determine causative roles for miR133a and LDLRAP1 in VSMC lipid uptake, proliferation, atherogenesis, cholesterol-induced phenotype modulation, and vascular restenosis.

Public Health Relevance

VSMC foam cell formation is an integral molecular event in atherosclerotic plaque reduction. Our preliminary and published data indicate two novel regulators of cholesterol uptake and proliferation in vascular smooth muscle cells; miR133a and LDLRAP1. The goals of this application are to clarify a causal effect between these two molecules, cholesterol uptake in VSMC, and development of vascular diseases.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Kirby, Ruth
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Temple University
Schools of Medicine
United States
Zip Code
Ray, Mitali; Gabunia, Khatuna; Vrakas, Christine N et al. (2018) Genetic Deletion of IL-19 (Interleukin-19) Exacerbates Atherogenesis in Il19-/-×Ldlr-/- Double Knockout Mice by Dysregulation of mRNA Stability Protein HuR (Human Antigen R). Arterioscler Thromb Vasc Biol 38:1297-1308
Autieri, Michael V (2018) IL-19 and Other IL-20 Family Member Cytokines in Vascular Inflammatory Diseases. Front Immunol 9:700
Ray, Mitali; Autieri, Michael V (2017) Regulation of pro- and anti-atherogenic cytokines. Cytokine :
Kermani, Golriz; Hemmasizadeh, Ali; Assari, Soroush et al. (2017) Investigation of inhomogeneous and anisotropic material behavior of porcine thoracic aorta using nano-indentation tests. J Mech Behav Biomed Mater 69:50-56
Gabunia, Khatuna; Herman, Allison B; Ray, Mitali et al. (2017) Induction of MiR133a expression by IL-19 targets LDLRAP1 and reduces oxLDL uptake in VSMC. J Mol Cell Cardiol 105:38-48
Herman, Allison B; Autieri, Michael V (2017) Inflammation-regulated mRNA stability and the progression of vascular inflammatory diseases. Clin Sci (Lond) 131:2687-2699
Bruns, Danielle R; Ghincea, Alexander R; Ghincea, Christian V et al. (2017) Interleukin-19 is cardioprotective in dominant negative cyclic adenosine monophosphate response-element binding protein-mediated heart failure in a sex-specific manner. World J Cardiol 9:673-684
Trappanese, Danielle M; Sivilich, Sarah; Ets, Hillevi K et al. (2016) Regulation of mitogen-activated protein kinase by protein kinase C and mitogen-activated protein kinase phosphatase-1 in vascular smooth muscle. Am J Physiol Cell Physiol 310:C921-30
Mai, Jietang; Nanayakkara, Gayani; Lopez-Pastrana, Jahaira et al. (2016) Interleukin-17A Promotes Aortic Endothelial Cell Activation via Transcriptionally and Post-translationally Activating p38 Mitogen-activated Protein Kinase (MAPK) Pathway. J Biol Chem 291:4939-54
Kako, Farah; Gabunia, Khatuna; Ray, Mitali et al. (2016) Interleukin-19 induces angiogenesis in the absence of hypoxia by direct and indirect immune mechanisms. Am J Physiol Cell Physiol 310:C931-41

Showing the most recent 10 out of 24 publications