As part of the VSMC response to injury, VSMC migrate into the lumen of the vessel where they proliferate and synthesize cytokines which they respond to in an autocrine fashion, sustaining the loss of lumen diameter. In the course of HL63810, we have determined that expression of Allograft Inflammatory Factor-1 (AIF-1), a newly described cytoplasmic, calcium-binding protein, is predictive of development of clinical transplant vasculopathy. Expression of AIF-1 in injured carotid artery significantly exacerbates reduction of lumen diameter and recruits bone marrow cells to the adventitia. Knock-down of AIF-1 abrogates neointimal hyperplasia. Expression of AIF-1 in human VSMC increases migration, proliferation, induces expression of G-CSF, and activates the Pad GTPase. AIF-1 contains several signaling domains, binds to and polymerizes actin, and activates signal transduction proteins. Our data support our central hypothesis that AIF-1 is an inflammation-responsive scaffold protein that plays a key role in regulation of VSMC activation and development of neointimal hyperplasia. The overall goals of this application are to 1- determine a cause and effect relationship between AIF-1 expression and neointimal hyperplasia in vivo, and 2- characterize the cellular pathways and molecular mechanisms responsible for AIF-1 activity in VSMC.
Three aims have been formulated to test the hypothesis that; 1- AIF-1 expression exacerbates neointimal hyperplasia, and that reduction of AIF-1 expression will reduce neointimal hyperplasia in angioplasty-injured rats and AIF-1 transgenic mice, 2- that AIF-1 directly activates Rac1 signaling pathways leading to G-CSF expression, and that AIF-1 directly activates G-CSF expression with a subsequent autocrine activation of the Rac signaling pathway, and 3- AIF-1 activates Rac1 by activation of GEFs, and induces G-CSF expression by activation of transcription factors. Characterization of AIF-1 function will clarify our understanding of inflammation-mediated signal transduction leading to VSMC pathobiology and vascular- immune cell cross talk. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL063810-05A2
Application #
7150122
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Massicot-Fisher, Judith
Project Start
1999-12-01
Project End
2010-06-30
Budget Start
2006-07-15
Budget End
2007-06-30
Support Year
5
Fiscal Year
2006
Total Cost
$337,500
Indirect Cost
Name
Temple University
Department
Physiology
Type
Schools of Medicine
DUNS #
057123192
City
Philadelphia
State
PA
Country
United States
Zip Code
19122
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Sommerville, Laura J; Kelemen, Sheri E; Ellison, Stephen P et al. (2012) Increased atherosclerosis and vascular smooth muscle cell activation in AIF-1 transgenic mice fed a high-fat diet. Atherosclerosis 220:45-52
Takaguri, Akira; Kimura, Keita; Hinoki, Akinari et al. (2011) A disintegrin and metalloprotease 17 mediates neointimal hyperplasia in vasculature. Hypertension 57:841-5
Jain, Surbhi; Gabunia, Khatuna; Kelemen, Sheri E et al. (2011) The anti-inflammatory cytokine interleukin 19 is expressed by and angiogenic for human endothelial cells. Arterioscler Thromb Vasc Biol 31:167-75
Hinoki, Akinari; Kimura, Keita; Higuchi, Sadaharu et al. (2010) p21-activated kinase 1 participates in vascular remodeling in vitro and in vivo. Hypertension 55:161-5
Cuneo, Anthony A; Herrick, David; Autieri, Michael V (2010) Il-19 reduces VSMC activation by regulation of mRNA regulatory factor HuR and reduction of mRNA stability. J Mol Cell Cardiol 49:647-54
Cuneo, Anthony A; Autieri, Michael V (2009) Expression and function of anti-inflammatory interleukins: the other side of the vascular response to injury. Curr Vasc Pharmacol 7:267-76
Suzuki, Hiroyuki; Kimura, Keita; Shirai, Heigoro et al. (2009) Endothelial nitric oxide synthase inhibits G12/13 and rho-kinase activated by the angiotensin II type-1 receptor: implication in vascular migration. Arterioscler Thromb Vasc Biol 29:217-24
Sommerville, Laura J; Xing, Chen; Kelemen, Sheri E et al. (2009) Inhibition of allograft inflammatory factor-1 expression reduces development of neointimal hyperplasia and p38 kinase activity. Cardiovasc Res 81:206-15
Tian, Ying; Jain, Surbhi; Kelemen, Sheri E et al. (2009) AIF-1 expression regulates endothelial cell activation, signal transduction, and vasculogenesis. Am J Physiol Cell Physiol 296:C256-66

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