The overall goals of this application are to demonstrate that Interleukin-19 (IL-19), a Th2 anti- inflammatory interleukin, can attenuate atherosclerosis, and identify the potential mechanisms of this inhibition. IL-19 is a newly described Th2, (T regulatory) anti-inflammatory interleukin which until our work, had been ascribed to be inflammatory cell-specific. We remain the only laboratory to investigate a role for this interleukin in vascular biology, particularly with respect to EC and VSMC pathophysiology, and to demonstrate molecular mechanisms for these effects. We previously reported that;1- IL-19 is not detectible in normal artery, but is induced in EC and VSMC in human atherosclerotic lesions;2- addition of IL-19 to VSMC reduces their migration, proliferation, and abundance of proliferative and inflammatory proteins;3- IL-19 does NOT inhibit NF-kB, but does reduce the stability of inflammatory and proliferative mRNA transcripts in an HuR-dependent manner;4- IL-19 induces expression of the vascular and cyto-protective protein Hemeoxygenase-1 (HO-1), and reduces apoptosis induced by vascular reactive oxygen species (ROS) in an HO-1 dependent manner. In this application we present preliminary data showing that addition of recombinant IL-19 to LDLR-/- mice fed an atherogenic diet significantly and dramatically decreases atherosclerotic plaque, and IL-19-/- mice have an exacerbated response to ligation injury. Based on published and preliminary data, we hypothesize that there are multiple, pleiotropic mechanisms for these protective effects, and Specific Aims are designed to test each of these mechanisms.
In Aim 1, we will determine if absence of IL-19 exacerbates, and if over expression attenuates atherosclerosis.
Aim 2 will test the hypothesis that one mechanism of IL-19 protection is primarily facilitated by adoptive immune system polarization to Th2.
Aim 3 will test the hypothesis that IL-19 atheroprotection is mediated by reduction in leukocyte-endothelial cell interaction, and/or IL-19 induction of HO-1 expression.
Aim 4 will determine the molecular mechanisms of how IL- 19 decreases inflammatory gene abundance. This application is potentially paradigm-changing as it will implicate a Th2 interleukin as an endogenous cytokine expressed by inflamed vascular cells with multiple autocrine and paracrine dampening effects. It will identify novel molecular mechanisms and targets of anti-inflammatory pathways in these cells.
Atherosclerotic vascular disease continues to account for 50% of all mortality in the United States. Interleukin-19 (IL-19) is a newly described anti-inflammatory interleukin expressed in injured arteries. The overall goal of this application is to test the hypothesis that IL-19 can be protective and inhibit atherosclerosis and determine the mechanisms.
|Gabunia, Khatuna; Ellison, Stephen; Kelemen, Sheri et al. (2016) IL-19 Halts Progression of Atherosclerotic Plaque, Polarizes, and Increases Cholesterol Uptake and Efflux in Macrophages. Am J Pathol 186:1361-74|
|Richards, James; Gabunia, Khatuna; Kelemen, Sheri E et al. (2015) Interleukin-19 increases angiogenesis in ischemic hind limbs by direct effects on both endothelial cells and macrophage polarization. J Mol Cell Cardiol 79:21-31|
|Gabunia, Khatuna; Autieri, Michael V (2015) Interleukin-19 can enhance angiogenesis by Macrophage Polarization. Macrophage (Houst) 2:e562|
|Miller, V; Lin, A; Kako, F et al. (2015) Microsecond-pulsed dielectric barrier discharge plasma stimulation of tissue macrophages for treatment of peripheral vascular disease. Phys Plasmas 22:122005|
|Ellison, Stephen; Gabunia, Khatuna; Richards, James M et al. (2014) IL-19 reduces ligation-mediated neointimal hyperplasia by reducing vascular smooth muscle cell activation. Am J Pathol 184:2134-43|
|Ellison, Stephen; Gabunia, Khatuna; Kelemen, Sheri E et al. (2013) Attenuation of experimental atherosclerosis by interleukin-19. Arterioscler Thromb Vasc Biol 33:2316-24|
|England, Ross N; Preston, Kyle J; Scalia, Rosario et al. (2013) Interleukin-19 decreases leukocyte-endothelial cell interactions by reduction in endothelial cell adhesion molecule mRNA stability. Am J Physiol Cell Physiol 305:C255-65|
|Mancarella, Salvatore; Potireddy, Santhi; Wang, Youjun et al. (2013) Targeted STIM deletion impairs calcium homeostasis, NFAT activation, and growth of smooth muscle. FASEB J 27:893-906|
|Autieri, Michael V (2013) Increasing our IQ of vascular smooth muscle cell migration with IQGAP1. Focus on ""IQGAP1 links PDGF receptor-Î² signal to focal adhesions involved in vascular smooth muscle cell migration: role in neointimal formation after vascular injury"". Am J Physiol Cell Physiol 305:C579-80|
|Hemmasizadeh, Ali; Autieri, Michael; Darvish, Kurosh (2012) Multilayer material properties of aorta determined from nanoindentation tests. J Mech Behav Biomed Mater 15:199-207|