Inflammation is critical to the initiation and progression of atherosclerosis and to the vascular response(s) to injury. Chemokines and their receptors contribute to inflammatory responses by mediating leukocyte trafficking and function. We have demonstrated that human arterial smooth muscle cells (SMC), the major cellular components of the vessel wall, possess the functional chemokine receptors, CCR5, and CXCR4. Engagement of these receptors results in a marked induction of tissue factor (TF) activity. TF is the initiator of the coagulation cascade and its activity is the likely proximate cause of clinical events such as heart attack and stroke. Macrophage inflammatory protein-1 beta (MIP-1beta, CCL4) and stromal cell-derived protein (SDF-1, CXCL12) are the endogenous ligands for CCR5 and CXCR4, respectively. Both the receptors and ligands are present in the SMC-rich areas of the human atherosclerotic plaque. CCR5 and CXCR4 are also the major co-receptors for human immunodeficiency disease (HIV) in vivo, and are responsible for HIV transmission and pathogenicity. Recently, reports of acute coronary thrombotic events indicate that patients with HIV may be prone to accelerated coronary artery disease. We have demonstrated that human arterial SMC are activated and infected by HIV.
Aim 1 will examine the induction of TF by MIP-1beta, SDF-1, and HIV envelope protein, gp120, and identify the endogenous- and HIV-CCR5 and -CXCR4 receptor-specific elements of the TF promoter.
Aim 2 will establish the repertoire of CCR5- and CXCR4-mediated functions in SMC, focusing on those that are relevant to atherosclerosis and that are mediated by the signaling pathways we identified to be involved in chemokine receptor engagement.
Aim 3 will examine the effect of HIV proteins on the vasculature using transgenic mice expressing HIV proteins, including gp120, and the HIV co-receptors, human CCR5 and human CD4. Mice will then be studied in a hyperlipidemic milieu to test the hypothesis that HIV, in the presence of its receptors, accelerates atherosclerosis and results an exaggerated response to injury. These studies will contribute to an understanding of the role of chemokine receptors and HIV in the induction of TF, the mediation of inflammatory responses of SMC, and the pathogenesis of atherosclerosis. Furthermore, given that HIV patients appear to have accelerated atherosclerosis, these studies will provide potential mechanism(s) responsible for HIV-associated vasculopathies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL073458-04
Application #
7046942
Study Section
Pathology A Study Section (PTHA)
Program Officer
Mcdonald, Cheryl
Project Start
2003-05-01
Project End
2008-04-30
Budget Start
2006-05-01
Budget End
2007-04-30
Support Year
4
Fiscal Year
2006
Total Cost
$413,792
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
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Schecter, Alison D; Berman, Adriane B; Yi, Lin et al. (2004) MCP-1-dependent signaling in CCR2(-/-) aortic smooth muscle cells. J Leukoc Biol 75:1079-85