Transplantation-associated arteriosclerosis (TAA) is the major cause of death in recipients who survive more than one year after cardiac transplantation. TAA is characterized by infiltration of inflammatory cells followed by the formation of a diffuse, concentric neointima in which smooth muscle cells and macrophages accumulate. Cells of the immune system-particularly the macrophage-play a key role in TAA. Through elaboration of inflammatory cytokines/ growth factors and release of proteolytic enzymes and chemokines, activated macrophages are critical to TAA. As such, identification of factors that regulate macrophage activation is of critical importance. Members of the Kruppel-like family of factors are transcription factors which play important roles in regulating cell differentiation and activation. We identified a member of this family termed KLF4 whose expression is highly expressed in macrophages associated with heart transplant lesions in vivo. KLF4 expression correlates with the induction of activated macrophages in response to interferon-gamma and is decreased in response to the anti-inflammatory growth factor, transforming growth factor-betal (TGF-b1). KLF4 overexpression in macrophages potently induces markers of macrophage activation such as iNOS and inhibits effects mediated by TGF-b1. These observations have led us to the central hypothesis that KLF4 serves as a critical regulator of macrophage activation and TAA.
In AIM1 of this proposal we explore the mechanistic basis for KLF4's ability to inhibit TGF-b1 signaling.
In AIM2, we examine the ability of KLF4 to induce macrophage iNOS gene expression. Finally, in AIMS, we assess the consequences of KLF4 overexpression on the development of TAA and on macrophage effector functions. These studies will provide important insight regarding the role of KLF4 in regulating macrophage activation. The results of these studies are of considerable scientific interest and may serve as the basis for novel therapeutic strategies to modulate TAA and the macrophage response to cytokine stimulation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL080174-05
Application #
7743766
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Sopko, George
Project Start
2006-01-01
Project End
2011-11-30
Budget Start
2009-12-01
Budget End
2011-11-30
Support Year
5
Fiscal Year
2010
Total Cost
$410,248
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
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