A dramatic clinical example of where disruption of the extracellular matrix within the cardiovascular system leads to a devastating disease process is thoracic aortic aneurysms (TAAs). Surgical reconstruction/endovascular interventions are possible for TAAs, but are in and of themselves high risk and do not affect the underlying pathways which drive this devastating disease. This laboratory and others have demonstrated that a specific cassette of proteolytic enzymes, the matrix metalloproteinases (MMPs), are increased in patients with TAAs.Using a murine TAA model developed by this laboratory, a cause-effect relationship was demonstrated between TAA progression and MMP induction/activational states. However, it remains unclear how and which MMP types are causative to these ECM changes and contribute to TAA progression. We have recently identified that a unique MMP, membrane type-1 (MT1-MMP) was upregulated with TAA progression and was accompanied by a loss in ECM architecture, interstitial vascular fibrosis, and a switch of thoracic aortic fibroblasts to a myofibroblast phenotype. Our new results have established that MT1-MMP cleaves the latent transforming growth factor-beta (TGF) binding protein-1 (LTBP-1), which would in turn enhance signaling of this potent profibrotic signaling pathway. Thus, the central hypothesis of this study is that the induction of MT1-MMP contributes to the natural history of TAAs in a bi-phasic manner- initiation due to enhanced ECM proteolysis, - and progression through an altered fibroblast phenotype and abnormal collagen accumulation which is an MT1-MMP/TGF driven process. This hypothesis will be addressed through the following specific aims: (1) Through transgenic reduction and amplification of MT1-MMP, establish that early induction of MT1-MMP primarily causes a localized and amplified MMP proteolytic response and initiates the TAA, whereas prolonged MT1- MMP induction causes heightened profibrotic signaling through an LTBP-TGF mechanism thereby sustaining ECM remodeling and TAA progression. (2) Using RNA interference (siRNA), demonstrate the early induction of MT1-MMP promoter activity in TAA progression results in a net amplification of MMP proteolytic activity and a loss of ECM structural integrity. (3) Establish that prolonged MT1-MMP induction causes a phenotypic switch in aortic fibroblasts, whereby selective targeting of fibroblast specific MT1-MMP will directly attenuate TAA progression. These studies will establish how a transmembrane proteolytic pathway contributes to TAA propagation and thereby provide new insights for the development of diagnostic and therapeutic strategies for this insidious and clinically devastating disease.

Public Health Relevance

A common disease of the thoracic aorta, causing a loss of its uniform structure by expansion, dilation, and possible rupture, is termed thoracic aortic aneurysm disease. This study will identify how molecules within the wall of the aorta can cause destruction of the aortic wall and induce an aneurysm formation. Because there is no cure for this disease, this study will be the first to identify how we might be able to predict and stop thoracic aortic aneurysms before the aorta ruptures, thereby saving lives of patients with this disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL102121-04
Application #
8586540
Study Section
Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
Program Officer
Tolunay, Eser
Project Start
2010-12-01
Project End
2014-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
4
Fiscal Year
2014
Total Cost
$331,875
Indirect Cost
$106,875
Name
Medical University of South Carolina
Department
Surgery
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
Ikonomidis, John S; Ivey, Charlotte R; Wheeler, Jason B et al. (2013) Plasma biomarkers for distinguishing etiologic subtypes of thoracic aortic aneurysm disease. J Thorac Cardiovasc Surg 145:1326-33
Ruddy, Jean Marie; Jones, Jeffery A; Ikonomidis, John S (2013) Pathophysiology of thoracic aortic aneurysm (TAA): is it not one uniform aorta? Role of embryologic origin. Prog Cardiovasc Dis 56:68-73
Theruvath, Tom P; Jones, Jeffrey A; Ikonomidis, John S (2012) Matrix metalloproteinases and descending aortic aneurysms: parity, disparity, and switch. J Card Surg 27:81-90
Jones, Jeffrey A; Stroud, Robert E; O'Quinn, Elizabeth C et al. (2011) Selective microRNA suppression in human thoracic aneurysms: relationship of miR-29a to aortic size and proteolytic induction. Circ Cardiovasc Genet 4:605-13