The vascular endothelium produces numerous growth factors, cytokines, and bioactive mediators that critically regulate vascular homeostasis in health and disease. During the previous funding period, we provided evidence that expression of the transcription factor KLF2 in endothelial cells is induced by biomechanical stimuli such as laminar shear stress (LSS) and pharmacologic stimuli such as 3- hydroxyl-3-methyglutaryl coenzyme A reductase inhibitors (also known as statins). We also demonstrated that this induction of KLF2 by both stimuli was dependent on members of the MEF2 family of transcription factors. Studies aimed at elucidating KLF2 function in endothelial cell biology indicate that this factor directly regulates the expression of potent anti-inflammatory and anti-thrombotic factors such as thrombomodulin (TM) and endothelial nitric oxide synthase (eNOS). Importantly, evidence was also provided that the ability of laminar flow or statins to induce TM and eNOS was KLF2 dependent. Finally, our studies demonstrated that KLF2 can inhibit cytokine-mediated induction of pro- inflammatory and pro-thrombotic factors (e.g. tissue factor and plasminogen activator inhibitor-1) through its ability to reduce NF?B activity. Consistent with this effect, KLF2 overexpression increased blood-clotting time while knockdown of KLF2 reduced blood-clotting time. Taken together, these studies provide the basis for this renewal application that will explore the role of KLF2 in greater detail.
In Aim 1, we will explore the molecular basis for flow and statin-mediated induction of KLF2 in vitro and in vivo.
In Aim 2, we will determine the molecular basis of KLF2 mediated-induction of target genes and the functional consequences of KLF2 deficiency on vascular thrombosis in vivo. And finally, in Aim 3, we will determine the molecular basis of KLF2 mediated-inhibition of proinflammatory target genes and the functional consequences of KLF2-deficiency on atherothrombosis in vivo. We anticipate that these studies will provide novel and fundamental insights regarding the role of KLF2 in endothelial cell biology. Furthermore, a greater understanding of KLF2 function in the context of statins may provide the foundation for novel therapeutic strategies aimed at the treatment of vascular inflammatory and thrombotic disease states. Narrative: Despite maximal medical therapy, cardiovascular disease remains the number one cause of morbidity and mortality in our society. As such the identification of novel treatment strategies is clearly required. Current paradigms suggest that dysfunction of the vascular endothelial cell that lines all blood vessels is a critical early event in the pathogenesis of blood vessel diseases. Our studies have identified a genetic factor that can confer favorable properties to endothelial cells and is induced by a class of medications termed statins. Our efforts are focused on developing a greater understanding of this factors role in endothelial cells with the hope that such investigations may provide the foundation for novel therapeutic strategies aimed at the treatment of vascular inflammatory disease states.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL076754-08
Application #
8300954
Study Section
Special Emphasis Panel (ZRG1-CVS-F (02))
Program Officer
Srinivas, Pothur R
Project Start
2004-08-01
Project End
2013-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
8
Fiscal Year
2012
Total Cost
$388,575
Indirect Cost
$141,075
Name
Case Western Reserve University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
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