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 #
5R01HL115103-02
Application #
8690961
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Evans, Frank
Project Start
2013-07-01
Project End
2018-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
2
Fiscal Year
2014
Total Cost
$379,064
Indirect Cost
$134,064
Name
Vanderbilt University Medical Center
Department
Pediatrics
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
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; Peacock, Jon R; Branch, Janelle et al. (2015) Biophysical analysis of dystrophic and osteogenic models of valvular calcification. J Biomech Eng 137:020903
Bowler, Meghan A; Merryman, W David (2015) In vitro models of aortic valve calcification: solidifying a system. Cardiovasc Pathol 24:1-10
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
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
Schroer, Alison K; Merryman, W David (2015) Mechanobiology of myofibroblast adhesion in fibrotic cardiac disease. J Cell Sci 128:1865-75
Sewell-Loftin, Mary Kathryn; DeLaughter, Daniel M; Peacock, Jon R et al. (2014) Myocardial contraction and hyaluronic acid mechanotransduction in epithelial-to-mesenchymal transformation of endocardial cells. Biomaterials 35:2809-15
Hutcheson, Joshua D; Aikawa, Elena; Merryman, W David (2014) Potential drug targets for calcific aortic valve disease. Nat Rev Cardiol 11:218-31

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