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.
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.
|Ikonomidis, John S; Nadeau, Elizabeth K; Akerman, Adam W et al. (2016) Regulation of membrane type-1 matrix metalloproteinase activity and intracellular localization in clinical thoracic aortic aneurysms. J Thorac Cardiovasc Surg :|
|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|
|DeNino, Walter F; Toole, John Matthew; Rowley, Christopher et al. (2014) Comparison of David V valve-sparing root replacement and bioprosthetic valve conduit for aortic root aneurysm. J Thorac Cardiovasc Surg 148:2883-7|
|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|
|Kavarana, Minoo N; Jones, Jeffrey A; Stroud, Robert E et al. (2014) Pulmonary arteriovenous malformations after the superior cavopulmonary shunt: mechanisms and clinical implications. Expert Rev Cardiovasc Ther 12:703-13|
|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|
|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|
|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|
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