Vascular restenosis induced by arterial trauma is one of the most critical factors which limits the success o solid organ transplantation and coronary interventional procedures. A popular hypothesis is that the cytokine-induced activation and proliferation of VSMC in the media, culminating in intimal hyperplasia, is the most critical cellular event in formation of both cardiac allograft vasculopathy (CAV) and balloon angioplastyinduced restenosis. Identification and functional characterization gene products involved in VSMC activation is a promising approach for the identification of targets to combat proliferative arteriopathy observed in vascular proliferative disorders. Our hypothesis is that allograft inflammatory factor-I (AIF-1) promotes development of vascular proliferative disease based on its ability to respond to inflammatory cytokines and participate in the growth stimulatory pathways leading to proliferation of VSMC. We have recently shown that modulation of AIF- 1 levels in human VSMC impacts the growth of these cells.
The first aim of this project will determine the mechanism of AIF-l growth promoting effects in human VSMC through a combination of flow cytometric analysis and investigation of expression and turnover of cell cycle-associated proteins. We will also identify regions that mediate these effects by site-specific modification of the AIF- 1 protein. We have determined that AIF- 1 partners with several cytoplasmic proteins, including a newly described growth factor-activated lipid kinase termed LCBK5.
The second aim of this proposal will determine the functional significance of the AIF- 1-LCBK5 interaction and characterize the other AIF-1-interacting peptides we have identified. Expression of AIF- 1 transcript is induced in mitogen-stimulated peripheral blood lymphocytes (PBL), and its expression in endomyocardial biopsies from transplanted hearts correlates with ISHLT rejection scores.
A final aim of this proposal will correlate AIF-1 transcript levels in endomyocardial biopsies and PBL from heart transplant recipients with development of arteriopathy as determined by several clinical and imaging indices. It is anticipated that completion of these studies will implicate expression of this novel protein as a target of anti-restenotic therapy and a surrogate marker of transplant restenosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL063810-03
Application #
6637512
Study Section
Pathology A Study Section (PTHA)
Program Officer
Massicot-Fisher, Judith
Project Start
2001-03-20
Project End
2005-02-28
Budget Start
2003-03-01
Budget End
2004-02-29
Support Year
3
Fiscal Year
2003
Total Cost
$263,375
Indirect Cost
Name
Temple University
Department
Physiology
Type
Schools of Medicine
DUNS #
057123192
City
Philadelphia
State
PA
Country
United States
Zip Code
19122
Berglund, Lisa M; Kotova, Olga; Osmark, Peter et al. (2012) NFAT regulates the expression of AIF-1 and IRT-1: yin and yang splice variants of neointima formation and atherosclerosis. Cardiovasc Res 93:414-23
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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