Our overarching hypothesis is that FXR1 activity may be a compensatory, anti-inflammatory activity in VSMC. Vascular smooth muscle cells (VSMC) play a critical role in the etiology and progression of many vascular diseases including atherosclerosis and restenosis. Reduction of inflammatory gene expression in VSMC is a rational approach to limit the severity of these diseases. Our laboratory has found that one anti-inflammatory interleukin, IL-19, can decrease vascular inflammation by reduction in mRNA stability of inflammatory transcripts by reduction of activity of HuR, an mRNA stability protein. HuR translocates from the nucleus to the cytoplasm where it recognizes elements present almost exclusively in the 3'UTR of pro-inflammatory genes. Proteins and pathways which limit HuR translocation may reduce inflammatory mRNA stability, but are currently understudied. Using LC-MS/MS to identify HuR-interacting proteins under different inflammatory conditions, we identified one protein termed Fragile X-related protein (FXR1), which interacts with HuR in inflammatory, but not basal conditions, a novel finding. Importantly, FXR1 mRNA expression is enhanced in muscle cells, and it's promoter contains multiple cholesterol-response elements. Nothing has been reported on expression of FXR1 in VSMC or function for FXR1 in vascular disease. We present preliminary data showing that FXR1 expression is increased in injured arteries and TNF? and oxLDL stimulated human VSMC, and this expression is increased by IL-19. We show that siRNA knock down of FXR1 in VSMC increases inflammatory mRNA stability, abundance of inflammatory proteins, and cholesterol uptake, while over-expression of FXR1 decreases mRNA stability and inflammatory protein abundance. Our hypothesis is that FXR1 expression is a compensatory, negative-regulatory mechanism and functions by decreasing HuR activity and vascular inflammation by decreasing the stability of pro-inflammatory transcripts by numerous mechanisms. The overall goal of this application is twofold: 1- to identify the molecular mechanisms of FXR1 function in regulation of HuR activity and mRNA stability of pro-inflammatory transcripts in VSMC, and; 2- determine if modulation of FXR1 activity can reduce severity of atherosclerosis and vascular restenosis.

Public Health Relevance

The majority of cells in atherosclerotic lesions are vascular smooth muscle cell (VSMC)-derived, and inflammatory gene expression in these cells regulates vascular disease. Our overarching hypothesis is that Fragile X related protein-1 (FXR1) activity may be a compensatory, anti-inflammatory gene regulatory factor in VSMC. This grant will determine the molecular mechanisms of how FXR1 modulates inflammatory gene abundance in VSMC, and regulate atherosclerosis and restenosis in vivo.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
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Kirby, Ruth
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Temple University
Internal Medicine/Medicine
Schools of Medicine
United States
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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

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