Age-related heart valve disease is the 3rd leading cause of cardiovascular disease and is especially prevalent among the elderly. Studies have shown that degenerative aortic valve disease affects over 25% of people over 65 years of age, leading to calcific aortic valve disease (CAVD) in 4-8 years. Currently, the only effective long- term treatment for advanced CAVD is valve replacement surgery, an invasive, high-risk procedure for elderly patients. For this reason, a non-invasive therapeutic to stop the progression of CAVD would greatly benefit those most at risk for developing severe CAVD. At the cellular level, CAVD is believed to be initiated by activation of AV interstitial cells (AVICs)to a myofibroblast phenotype. Once activated, these cells increase extracellular matrix deposition, particularly type I collagen, which directly leads to decreased compliance of the leaflets observed in CAVD. Transforming growth factor-b1 (TGF-b1) has been the most extensively studied cytokine initiator of CAVD;however, serotonin (5-HT) and other serotonergic receptor agonists have been shown to lead to CAVD upstream of TGF-b1 through signaling at the serotonergic receptor, 5-HT2B. Genetically, NOTCH1 haploinsufficiency results in CAVD with 100% penetrance in human patients. Notch1+/- leads to increased synthesis and/or signaling of both BMP2 and TGF-b1 in the AV leaflets of mice, which results in CAVD. Therefore, Notch1+/- mice provide a clinically relevant animal model to examine strategies against CAVD. Here, we show evidence that 5-HT2B antagonism prevents phenotypic alteration of AVICs by TGF-b1 in vitro. Moreover, we present evidence that 5-HT2B antagonism prevents non-canonical TGF-b1 signaling in AVICs. We therefore hypothesize that 5-HT2B can be specifically antagonized to prevent AVIC myofibroblast activation and provide early time point molecular targets to treat CAVD and we will test this hypothesis in Notch1+/- animals and isolated AVICs both for these animals and humans. We anticipate that this research plan will demonstrate a novel treatment strategy for CAVD. Further, this research plan will elucidate the underlying molecular mechanism, while also quantifying biomechanical changes and functional hemodynamics due to 5-HT2B antagonism.
The only effective, long-term treatment for degenerative aortic valve disease is open-chest valve replacement surgery, which is highly undesirable for elderly patients. Thus, there is a pressing need to develop novel strategies for prevention or treatment that will reduce the number of open-chest surgery. The goal of this project is to develop serotonergic receptor targeted therapy that prevents aortic valve cells from becoming myofibroblasts, which are the hallmark of degenerative aortic valve disease that ultimately leads to calcific aortic valve disease.
|Bloodworth, Nathaniel C; Clark, Cynthia R; West, James D et al. (2018) Bone Marrow-Derived Proangiogenic Cells Mediate Pulmonary Arteriole Stiffening via Serotonin 2B Receptor Dependent Mechanism. Circ Res 123:e51-e64|
|Schroer, Alison K; Shotwell, Matthew S; Sidorov, Veniamin Y et al. (2017) I-Wire Heart-on-a-Chip II: Biomechanical analysis of contractile, three-dimensional cardiomyocyte tissue constructs. Acta Biomater 48:79-87|
|Vander Roest, Mark J; Merryman, W David (2017) A developmental approach to induced pluripotent stem cells-based tissue engineered heart valves. Future Cardiol 13:1-4|
|Clark, Cynthia R; Bowler, Meghan A; Snider, J Caleb et al. (2017) Targeting Cadherin-11 Prevents Notch1-Mediated Calcific Aortic Valve Disease. Circulation 135:2448-2450|
|Merryman, W David; Clark, Cynthia R (2016) Lnc-ing NOTCH1 to Idiopathic Calcific Aortic Valve Disease. Circulation 134:1863-1865|
|West, James D; Carrier, Erica J; Bloodworth, Nathaniel C et al. (2016) Serotonin 2B Receptor Antagonism Prevents Heritable Pulmonary Arterial Hypertension. PLoS One 11:e0148657|
|Chen, Joseph; Ryzhova, Larisa M; Sewell-Loftin, M K et al. (2015) Notch1 Mutation Leads to Valvular Calcification Through Enhanced Myofibroblast Mechanotransduction. Arterioscler Thromb Vasc Biol 35:1597-605|
|Chen, Joseph; Peacock, Jon R; Branch, Janelle et al. (2015) Biophysical analysis of dystrophic and osteogenic models of valvular calcification. J Biomech Eng 137:020903|
|Schroer, Alison K; Merryman, W David (2015) Mechanobiology of myofibroblast adhesion in fibrotic cardiac disease. J Cell Sci 128:1865-75|
|Bowler, Meghan A; Merryman, W David (2015) In vitro models of aortic valve calcification: solidifying a system. Cardiovasc Pathol 24:1-10|
Showing the most recent 10 out of 15 publications