Aortic aneurysms (AA) are the 13th leading cause of death in the U.S. Since no medical therapy exists to alter the progression of disease, understanding the pathogenesis of AA is an important undertaking. The hallmark of AAs includes inflammatory infiltration, matrix metalloproteinase (MMP) production by macrophages and smooth muscle cells (SMCs) leading to destruction of collagen and elastin in the aortic wall and vessel dilation. Our preliminary data suggests that SMCs undergo phenotypic switching defined by increased SMC production of MMPs and downregulation of SMC contractile marker genes prior to experimental aneurysm formation. The loss of Kruppel like factor-4 (KLF4) has been shown to delay phenotypic switching to an inflammatory phenotype in a ligation-induced model of vascular injury. Moreover, in this model, KLF4 loss resulted in hyperproliferation of medial SMCs. KLF4 appears to have opposing effects in macrophages and endothelial cells. Preliminary studies in our lab have documented KLF4 is profoundly elevated in human and experimental aneurysms by immunohistochemistry. The focus of this proposal is to test the hypothesis that KLF4 plays a key role in experimental aneurysms and that effects are mediated through actions of KLF4 in SMCs, macrophages, and/ or endothelial cells.
Aim 1 will determine if conditional KLF4 knockout mice show altered formation of aneurysms and if effects are mediated through effects in SMCs or in other cell types. We will utilize several unique transgenic knockout mice developed in the Owens (mentor's) lab as well as bone marrow reconstitution studies that will allow cell specific deletion of KLF4 and subject them to an experimental aneurysm formation using elastase perfusion.
Aim 2 will determine if epigenetic mechanisms contribute to the effects of KLF4 on aortic aneurysm formation. Studies will test the hypothesis that KLF4 contributes to suppression of SMC marker genes and activation of several inflammatory genes within aneurysms, by binding to promoters in each of these genes, mediating histone modifications association with transcriptional silencing and activation. Finally, we will determine if these epigenetic modifications in AA are KLF4 dependent using KLF4 knockout mice. PHS 398/2590 (Rev. 11/07) Page Continuation Format Page

Public Health Relevance

Program Director/Principal Investigator (Last, First, Middle): Ailawadi, Gorav Project Narrative/ Relevance There are no proven medical treatments to alter progression of aneurysm disease. KLF4 delays SMC phenotypic switching to an inflammatory state in models of vascular injury. Furthermore, KLF4 is highly upregulated in AA. Loss of KLF4 studies will allow us to determine the effect of KLF4 and SMC phenotype in the progression of disease and determine if this is a potential therapeutic target to slow AA progression.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Clinical Investigator Award (CIA) (K08)
Project #
Application #
Study Section
Special Emphasis Panel (ZHL1-CSR-U (O1))
Program Officer
Roltsch, Mark
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Virginia
Schools of Medicine
United States
Zip Code
Schaheen, Basil; Downs, Emily A; Serbulea, Vlad et al. (2016) B-Cell Depletion Promotes Aortic Infiltration of Immunosuppressive Cells and Is Protective of Experimental Aortic Aneurysm. Arterioscler Thromb Vasc Biol 36:2191-2202
Pope, Nicolas H; Salmon, Morgan; Davis, John P et al. (2016) D-series resolvins inhibit murine abdominal aortic aneurysm formation and increase M2 macrophage polarization. FASEB J 30:4192-4201
Pope, Nicolas H; Salmon, Morgan; Johnston, William F et al. (2015) Interleukin-6 Receptor Inhibition Prevents Descending Thoracic Aortic Aneurysm Formation. Ann Thorac Surg 100:1620-6
Johnston, William F; Salmon, Morgan; Pope, Nicolas H et al. (2014) Inhibition of interleukin-1? decreases aneurysm formation and progression in a novel model of thoracic aortic aneurysms. Circulation 130:S51-9
Meher, Akshaya K; Johnston, William F; Lu, Guanyi et al. (2014) B2 cells suppress experimental abdominal aortic aneurysms. Am J Pathol 184:3130-41
Pope, Nicolas H; Ailawadi, Gorav (2014) Transcatheter Mitral Valve Repair. Oper Tech Thorac Cardiovasc Surg 19:219-237
Pope, Nicolas H; Ailawadi, Gorav (2014) Minimally invasive valve surgery. J Cardiovasc Transl Res 7:387-94
Bhamidipati, Castigliano M; Whatling, Carl A; Mehta, Gaurav S et al. (2014) 5-Lipoxygenase pathway in experimental abdominal aortic aneurysms. Arterioscler Thromb Vasc Biol 34:2669-78
Bhamidipati, Castigliano M; Scott Lim, D; Ragosta, Michael et al. (2013) Percutaneous transjugular implantation of MELODY® valve into tricuspid bioprosthesis. J Card Surg 28:391-3
LaPar, Damien J; Gillen, Jacob R; Crosby, Ivan K et al. (2013) Predictors of operative mortality in cardiac surgical patients with prolonged intensive care unit duration. J Am Coll Surg 216:1116-23

Showing the most recent 10 out of 16 publications