Current projections indicate that the number of individuals 65 years and older is expected to double by the year 2030. Because thoracic aortic aneurysm (TAAs) occur most frequently in persons 60-70 years of age, it follows that over the next two decades the frequency of aneurysm disease diagnosis is going to increase dramatically. TAA disease is an insidious process which often causes death by rupture in the absence of antecedent symptomology. There are presently no available indices to determine which patients may be at greater risk for acceleration of TAA development, warranting more immediate treatment. Therefore, further diagnostic and therapeutic advancement is critical, especially for those patients who have not yet reached surgical criteria. TAA development proceeds by a multifactorial process that is regulated by both intracellular and extracellular mechanisms which drive the pathological remodeling of the aortic extracellular matrix (ECM). The matrix metalloproteinases (MMPs) are a family of proteolytic enzymes that play an obligate role in TAA-induced ECM remodeling. In addition to structural remodeling, changes in the cellular constituents have also been demonstrated, and recent data has identified the aortic fibroblast as a critical mediator. When age-dependent changes in aortic structure and composition are overlaid with other risk factors for aneurysm development, the threshold, severity, and prognosis of aneurysm disease is likely accelerated. Therefore, the present application proposes to test the central hypothesis that age-related changes in thoracic aortic aneurysm development are driven by alterations in signaling through the transforming growth factor-beta pathway and result in altered aortic extracellular matrix mediated by phenotypically unique fibroblasts. This hypothesis will be addressed through three specific aims: 1) Demonstrate that differential acceleration of TAA development in young and old mice is a direct result of structural and compositional differences in aortic substrate;2) Establish that age- dependent changes in TAA progression are a direct result of alterations in aortic fibroblast number, phenotype, and function;and 3) Establish that defects in TGF-b signaling are responsible for age-dependent changes in TAA progression in the "old" aorta. The outcomes from this project will establish that the structural and compositional changes in the aortic ECM of old mice are mediated by age-dependent defects in collagen and MMP/TIMP gene expression. These age-dependent changes are affected by reduced signaling through the TGF-b pathway and result in a weakened aortic substrate that is hyper-responsive to TAA stimuli. Collectively, these studies will provide significant insight toward understanding the pathophysiology of TAA development, and will form the basis for novel, rational drug design for therapeutic modulation of TAA progression in patients with this devastating disease.

Public Health Relevance

TAA disease is an insidious process which often causes death by rupture in the absence of any symptoms. There are no available indices to determine which patients may be at greatest risk for accelerated TAA development. This project will identify age-dependent defects within the aorta that result in a weakened aortic substrate that is hyper-responsive to TAA stimuli and thereby provide new insights for the development of diagnostic and therapeutic strategies for treating insidious and clinically devastating disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG036954-02
Application #
8324210
Study Section
Aging Systems and Geriatrics Study Section (ASG)
Program Officer
Zieman, Susan
Project Start
2011-09-01
Project End
2016-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
2
Fiscal Year
2012
Total Cost
$302,375
Indirect Cost
$97,375
Name
Medical University of South Carolina
Department
Surgery
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
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Mukherjee, Rupak (2016) Forewarned is forearmed: Benefits of remote ischemic preconditioning. J Thorac Cardiovasc Surg 151:786-7
Wheeler, Jason B; Mukherjee, Rupak; Stroud, Robert E et al. (2015) Relation of murine thoracic aortic structural and cellular changes with aging to passive and active mechanical properties. J Am Heart Assoc 4:e001744
Ikonomidis, John S (2015) Valve-sparing aortic root replacement: too many cooks? J Thorac Cardiovasc Surg 149:114-5
Ikonomidis, John S (2015) Do we have a novel, clinically applicable approach to spinal cord protection? J Thorac Cardiovasc Surg 149:586-7
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Wheeler, Jason B; Ikonomidis, John S; Jones, Jeffrey A (2014) Connective tissue disorders and cardiovascular complications: the indomitable role of transforming growth factor-beta signaling. Adv Exp Med Biol 802:107-27
Ikonomidis, John S (2014) Current status of cerebral protection for aortic arch surgery. J Thorac Cardiovasc Surg 148:2466-2467
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Kavarana, Minoo N; Mukherjee, Rupak; Eckhouse, Shaina R et al. (2013) Pulmonary artery endothelial cell phenotypic alterations in a large animal model of pulmonary arteriovenous malformations after the Glenn shunt. Ann Thorac Surg 96:1442-9

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