Thoracic aortic aneurysm (TAA) disease is a potentially devastating disease process which often causes death by rupture in the absence of symptoms. TAA formation proceeds by a multifactorial process, influenced by both cellular and extracellular mechanisms that result in alterations of the structure and composition of the extracellular matrix (ECM). There are currently no effective non-surgical clinical treatment protocols available which will halt or reverse the aortic remodeling process during aneurysm formation. While current data demonstrate that this pathological remodeling is a result of a significant spatiotemporal change in the expression/abundance of the matrix metalloproteinases and their endogenous tissue inhibitors, little attention has been focused on the upstream signaling events that regulate the remodeling process. One upstream signaling protein known to alter the structure and composition of the ECM, and known to play an important role in vascular remodeling is transforming growth factor-beta (TGF-b). Examination of the TGF-b signaling pathway during TAA development revealed a shift in signaling from a TGF-bRI-mediated pathway to an ALK-1- mediated pathway. Accordingly, the present proposal will test the central hypothesis that signaling through the ALK-1 pathway drives aberrant vascular remodeling and TAA development. Using a small animal model of TAA, cellular studies of isolated aortic fibroblasts, and in vivo delivery of specific genes/inhibitors, this hypothesis will be tested by: (1) establishing the relationship between alterations in TGF-b signaling and changes in the determinants of ECM degradation/deposition during TAA development;(2) demonstrating that alterations in MMP/TIMP expression and abundance are mediated by the effects of TGF-b on aortic fibroblasts;and (3) demonstrating that MMP/TIMP abundance and aortic dilatation can be altered by modifying TGF-b signaling in vivo. This unique set of proposed studies will establish the relationship between altered TGF-b signaling and the production of the degradative determinants of ECM remodeling. The outcomes of this proposal will provide exceptional insight into the development of TAA and may identify significant targets through which TAA formation and progression can be disrupted.
Thoracic aortic aneurysm (TAA) disease is a potentially devastating disease process which often lacks specific symptomology, rendering them unnoticed until the aorta ruptures, resulting in significant morbidity and mortality. Currently, there are no noninvasive interventional treatments available for TAA patients. A """"""""watch and wait"""""""" surveillance program is initiated until the risk of aortic rupture outweighs the risk of the surgical repair. With a growing concern of increased aneurysm incidence due to a rapidly aging Veterans population and a high prevalence for cardiovascular disease, further diagnostic and therapeutic advancement is critical. The present proposal will assess key components of the TGF-b signaling pathway, in an effort to understand the role of TGF-b signaling in the etiology of TAA disease. Elucidating the underlying mechanisms may assist in developing strategies to arrest TAA formation or even reverse TAA progression, and will carry significant diagnostic, prognostic, and therapeutic implications for Veteran's and the public at large.
|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|
|Ruddy, Jean Marie; Akerman, Adam W; Kimbrough, Denise et al. (2017) Differential hypertensive protease expression in the thoracic versus abdominal aorta. J Vasc Surg 66:1543-1552|
|Jones, Jeffrey A (2016) Editorial Commentary: Understanding Marfan syndrome, or ""how not to invent the light bulb"". Trends Cardiovasc Med 26:429-32|
|Ruddy, Jean Marie; Ikonomidis, John S; Jones, Jeffrey A (2016) Multidimensional Contribution of Matrix Metalloproteinases to Atherosclerotic Plaque Vulnerability: Multiple Mechanisms of Inhibition to Promote Stability. J Vasc Res 53:1-16|
|Jones, Jeffrey A (2015) Invited commentary. Ann Thorac Surg 99:71|
|Daskalova, Elena; Delchev, Slavi; Peeva, Yulia et al. (2015) Antiatherogenic and Cardioprotective Effects of Black Chokeberry (Aronia melanocarpa) Juice in Aging Rats. Evid Based Complement Alternat Med 2015:717439|
|Renaud, Ludivine; Harris, Lillianne G; Mani, Santhosh K et al. (2015) HDACs Regulate miR-133a Expression in Pressure Overload-Induced Cardiac Fibrosis. Circ Heart Fail 8:1094-104|
|McDonald, Lindsay T; Russell, Dayvia L; Kelly, Ryan R et al. (2015) Hematopoietic stem cell-derived cancer-associated fibroblasts are novel contributors to the pro-tumorigenic microenvironment. Neoplasia 17:434-48|
|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|
|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|
Showing the most recent 10 out of 11 publications