The aortic wall is a tightly regulated structure that performs essential functions in a unique hemodynamic environment. Aortic wall homeostasis involves interactions between major structural components and its predominant cellular constituent - the vascular smooth muscle cell. Perturbation of these homeostatic mechanisms secondary to genetic and/or environmental factors can lead to permanent dilatations termed aorta aneurysms (AA). Insights gleaned from clinical, pathologic, and experimental studies indicate that local inflammation of the aorta, fragmentation of the extracellular matrix, and loss f smooth muscle cells are central features of AA. These lesions may occur in both the thoracic and abdominal regions of the aortic tree and can deteriorate to vascular dissection and/or rupture that constitute a significant source of morbidity and mortality. While the molecular pathways governing AA formation remain poorly understood, accumulating evidence implicates activation of the renin-angiotensin system (RAS) as an important contributor to the pathogenesis of AA disease. However, current pharmacotherapies targeting this pathway and others have demonstrated only modest effects suggesting that greater insights into the pathobiology of this disease entity are required to develop effective therapies. Recently published work from our group coupled with nascent observations provided in this application identify the transcription factor Kruppel-like factor 15 (KLF15) as an essential regulator of AA formation. KLF15 expression was found to be strongly reduced in human AA tissues and in aortas of mice following angiotensin II (Ang II) infusion. Mice deficient in KLF15 develop AA characterized by elastin fragmentation, vascular inflammation/dissection, and SMC apoptosis following Ang II infusion. Mechanistically, our studies reveal that KLF15 deficiency increased the levels and activity of p53, a key regulator of smooth muscle cell inflammation and survival. The importance of p53 is underscored by the observation that compound deficiency of KLF15 and p53 ameliorates AA formation. Collectively, these observations provide cogent evidence implicating a previously unrecognized transcriptional axis - that of KLF15/p53 - as critical to the pathogenesis of AA disease. To better understand the role of KLF15 in aneurysmal biology three robust and interrelated aims are proposed.
In aim 1, we will assess the effect of vascular specific manipulation of the KLF15-p53 axis on AA formation.
In aim 2, we seek to elucidate the molecular mechanism underlying KLF15-mediated alterations in p53 acetylation and activity in vitro. And finally, in aim 3, we will determine the in vivo role of KLF15-dependent regulation of p53 acetylation/activity in AA formation. Collectively, these studies will provide novel insights regarding a previously unappreciated transcriptional pathway governing aortic aneurysm development. Further, the results of these studies may provide the foundation for novel approaches to the treatment of this highly morbid and mortal disease.

Public Health Relevance

Aortic aneurysms are a major cause of morbidity and mortality worldwide. The mechanisms underlying the development of aortic aneurysms remain poorly understood and, consequently, hampered the development of effective medical therapies. Recent studies from our group have identified a previously unrecognized molecular pathway regulating aneurysm formation. This proposal seeks to develop a detailed understanding of this pathway with the goal of developing novel therapies for the treatment of this highly mortal condition.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL112486-03
Application #
8675932
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Tolunay, Eser
Project Start
2012-07-01
Project End
2016-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
3
Fiscal Year
2014
Total Cost
$488,129
Indirect Cost
$180,161
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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