Thoracic aortic aneurysms (TAAs), a generally asymptomatic process, develop as a consequence to abnormal remodeling of the aortic extracellular matrix (ECM) which weakens the aortic wall and leads to gross dilation that typically progresses to rupture. Currently, the treatment options consist of surgical reconstruction or endovascular intervention; neither of which addresses the underlying pathways which drive this devastating disease. TAAs are influenced by both intracellular and extracellular mechanisms that function to regulate matrix deposition and degradation, in part through the activation of the matrix metalloproteinases (MMPs). Previously, we identified membrane type-1 MMP (MT1-MMP) as a key mediator of TAA formation, through its role in both pericellular proteolysis and intracellular signaling. Utilizing murine model of TAA, protein levels of MT1-MMP increased during TAA development and localized to aortic fibroblasts. Moreover, MT1- MMP activity displayed a direct relationship with aortic dilatation. Importantly, when TAAs were induced in MT1-MMP heterozygous deficient mice, aortic dilatation was attenuated, suggesting it is required for TAA progression. Nevertheless, little is known in regards to the mechanisms that regulate the temporal expression, abundance, and activity of MT1-MMP during TAA development. MicroRNAs (miRs) have recently been identified as upstream mediators involved in the post-transcriptional regulation of protein production. We have demonstrated a loss in miR-133a expression, a validated miR that targets MT1-MMP translation, during TAA development. This loss of miR-133a displayed an inverse relationship with aortic size and coincided with an increase in MT1-MMP protein. Furthermore, several studies have suggested that MT1-MMP may be phosphorylated by protein kinase C and may play a role in regulating MT1-MMP activity through endocytosis. However, whether or not this phosphorylation may differentiate the multiple roles of MT1-MMP in regards to pericellular proteolysis and intracellular signaling remains to be defined. Accordingly, the central hypothesis of this proposal is that modulation of the dynamic regulation of MT1-MMP protein abundance, activity, and localization mediates TAA formation and progression, which will be examined with the following specific aims: (1) Demonstrate that MT1-MMP abundance and TAA development are regulated by changes in aortic fibroblast phenotype, mediated by changes in miR133a expression; (2) Demonstrate that pericellular proteolysis and intracellular signaling are mediated by changes in MT1- MMP cellular localization, regulated by phosphorylation of C-terminal residues. These studies will provide evidence for mechanistic changes that occur during TAA development, and will focus on both post-transcriptional and post-translational mechanisms that may reveal potential therapeutic targets.

Public Health Relevance

Outcomes from this study will identify critical components in the MT1-MMP regulatory pathway which are capable of interrupting aneurysm formation and progression. These studies will provide foundational evidence for mechanistic changes that occur during aneurysm development, focusing on both post-transcriptional and posttranslational mechanisms that may reveal potential therapeutic targets.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL102121-05A1
Application #
9070876
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Tolunay, Eser
Project Start
2010-04-01
Project End
2020-04-30
Budget Start
2016-05-01
Budget End
2017-04-30
Support Year
5
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Medical University of South Carolina
Department
Surgery
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29403
Ikonomidis, John S (2018) Sternotomy extra-anatomic bypass for stent-graft extension. J Thorac Cardiovasc Surg 155:913-914
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Henley, Megan D; Farber, Mark A; Ikonomidis, John S et al. (2018) A Tale of Three Surgeries: Management of a Massive Recurrent Mycotic Aortic Pseudoaneurysm. J Cardiothorac Vasc Anesth 32:550-557
Ikonomidis, John S (2017) Catch-22: Management of aortoesophageal fistula after thoracic endovascular aortic repair. J Thorac Cardiovasc Surg 154:787
Kalbaugh, Corey A; Ikonomidis, John S (2017) Cardiothoracic surgical training in Canada and the United States: Divergent paths, converging goals. J Thorac Cardiovasc Surg 154:1006-1007
Ikonomidis, John S (2017) Aortic surgery in Loeys-Dietz syndrome: Excellent results, but close surveillance is necessary. J Thorac Cardiovasc Surg 153:413-414
Ikonomidis, John S; Nadeau, Elizabeth K; Akerman, Adam W et al. (2017) Regulation of membrane type-1 matrix metalloproteinase activity and intracellular localization in clinical thoracic aortic aneurysms. J Thorac Cardiovasc Surg 153:537-546
Ikonomidis, John S (2017) Valve-sparing aortic root replacement: Surgeon and patient factors contribute to long-term durability. J Thorac Cardiovasc Surg 153:230-231
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Michler, Robert E; Smith, Peter K; Parides, Michael K et al. (2016) Two-Year Outcomes of Surgical Treatment of Moderate Ischemic Mitral Regurgitation. N Engl J Med 374:1932-41

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