The aortic wall is a highly organized and regulated structure that performs essential functions in a unique hemodynamic milieu. Maintenance of aortic wall structure and homeostasis involves interactions between major structural components and its cellular constituent - the vascular smooth muscle cell (SMC). Perturbation of these interactions secondary to genetic and/or environmental factors can lead to permanent dilatations termed aortic aneurysms (AA);a disease that accounts for 2% of deaths worldwide. Insights gleaned from clinical, pathologic, and experimental studies indicate that local inflammation of the aorta, fragmentation of the extracellular matrix, and loss of smooth muscle cells are central features in the initiation and progression AA. These lesions in both the thoracic and abdominal aorta can deteriorate resulting in dissection and /or rupture. 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 therapeutic benefit suggesting that greater insights into the pathobiology of this disease entity are required to develop effective treatments. CCN (Cyr61, Ctgf, Nov) family proteins are a group of secreted extracellular matrix-associated signaling proteins that are capable of mediating diverse biologic functions. However, the physiological functions of these proteins in the vasculature are largely unknown. Nascent observations from the applicant's laboratory identify CCN3 (a member of CCN family) as an essential regulator of AA formation. CCN3 expression was found to be strongly reduced in the rodent aorta following angiotensin II (Ang II) infusion, findings recapitulated in human AA tissues. Mice systemically deficient in CCN3 develop AA characterized by elastin fragmentation, vascular inflammation/dissection, and SMC apoptosis following Ang II infusion. Additionally, CCN3 deficiency dramatically increased the nuclear levels of NFkB, a key regulator of vascular SMC inflammation and survival. Lastly, we identify Kruppel-like factor 15 (KLF15), an essential determinant of AA formation, as an upstream regulator of CCN3 expression in SMC. Collectively, these observations provide cogent evidence implicating a previously unrecognized role for CCN3 in the pathogenesis of AA disease. To better understand the role of CCN3 in aneurysmal biology three robust and interrelated aims are proposed.
In Aim 1, we will fully characterize the role of CCN3 in aortic aneurysm formation.
In Aim 2, we seek to elucidate the molecular mechanism by which CCN3 deficiency leads to aortic aneurysm development. And finally, in Aim 3, we will determine the importance of CCN3 in AA formation in KLF15-KO animals. The results of these studies may provide the foundation for novel approaches to the treatment of this disease.

Public Health Relevance

Despite the high degree of morbidity and mortality associated with aortic aneurysm, medical options are woefully inadequate and urgent surgery is the only current therapy. Therefore, it is imperative that we elucidate the cellular and molecular basis for this disease in an effort to develop pharmacologic therapies. Studies in this proposal aim to address the role of a genetic factor termed CCN3 in aortic aneurysm development and the results may provide the foundation for novel approaches to ameliorate the aortic aneurysm development.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL117759-02
Application #
8669158
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Tolunay, Eser
Project Start
2013-06-01
Project End
2018-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
2
Fiscal Year
2014
Total Cost
$388,325
Indirect Cost
$143,325
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