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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL115103-03
Application #
8824962
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Evans, Frank
Project Start
2013-07-01
Project End
2016-03-31
Budget Start
2015-04-01
Budget End
2016-03-31
Support Year
3
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Pediatrics
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37240
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
Bowler, Meghan A; Merryman, W David (2015) In vitro models of aortic valve calcification: solidifying a system. Cardiovasc Pathol 24:1-10
Boronyak, Steven M; Monahan, Ken; Brittain, Evan L et al. (2015) An Inflection Point Method for the Determination of Pulmonary Transit Time From Contrast Echocardiography. IEEE Trans Biomed Eng 62:1853-61
Bloodworth, Nathaniel C; West, James D; Merryman, W David (2015) Microvessel mechanobiology in pulmonary arterial hypertension: cause and effect. Hypertension 65:483-9
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

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