Cellular Mechanisms of VIC Activation in Mitral Valve Prolapse

Bibliographic Details
Main Author:	Dye, Bailey Katherine
Language:	English
Published:	The Ohio State University / OhioLINK 2020
Subjects:	Biomedical Research Heart valve extracellular matrix heart valve interstitial cells myxomatous degeneration
Online Access:	http://rave.ohiolink.edu/etdc/view?acc_num=osu1594995213439086

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spelling	ndltd-OhioLink-oai-etd.ohiolink.edu-osu15949952134390862021-08-03T07:15:42Z Cellular Mechanisms of VIC Activation in Mitral Valve Prolapse Dye, Bailey Katherine Biomedical Research Heart valve extracellular matrix heart valve interstitial cells myxomatous degeneration Mitral valve prolapse (MVP) affects 3-6% of the total population including those with connective tissue disorders. Current treatment options are limited, and patients commonly require surgery which can be impermanent and insuperable. MVP is diagnosed as increased length and thickness of the mitral leaflets with abnormal prolapse of the leaflets into the left atria, often accompanied by mitral regurgitation due to the inability of the leaflets to close and coapt. This is due to compromised biomechanics of the leaflet, caused by disturbances to the composition and organization of the extracellular matrix (ECM), that weaken mechanical function. This process, known as myxomatous degeneration, is characterized by an abnormal accumulation of proteoglycans, in addition to collagen fiber disruption and elastic fiber fragmentation. The underlying mechanisms that promote myxomatous degeneration to the point of biomechanical failure are unknown. However, previous histological studies of end-stage diseased leaflet tissue have reported abnormal alpha-smooth muscle actin (SMA) expression in a subset of heart valve interstitial cells (VICs) characteristic of activated cells, and these cells are localized within regions of myxomatous ECM changes. As the contribution of activated, SMA-positive VICs to valve disease has not been explored, the goal of this study is to explore the regulation, and contribution of these abnormal cells in the progression of MVP pathogenesis. To do this, we utilized mice harboring a Fbn1C1039G mutation that mimic human features of Marfan Syndrome and develop MVP, to examine temporal and spatial changes in SMA expression relative to myxomatous degeneration via histological techniques. We showed that SMA-positive VICs are present prior to myxomatous degeneration and increase in number throughout disease progression. In vitro, we further showed that SMA is required for expression of Collagen I and proteoglycans via direct and indirect knockdown of SMA in VICs. Finally, upstream regulators of SMA were found to include mechanical stiffness via Rho/MRTF/SRF signaling, as well as a novel role for the bHLH transcription factor Scx, which we demonstrated is sufficient to increase SMA and cause abnormal ECM changes using a novel mouse model in vivo. Taken together, our data show that in VICs, SMA is important for mediating ECM remodeling associated with phenotypes observed in myxomatous degeneration, and further identify potential upstream regulators of this process. These novel insights could inform the development of future non-surgical therapeutics to halt the progression of mitral valve degeneration thereby avoiding end-stage prolapse. 2020 English text The Ohio State University / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=osu1594995213439086 http://rave.ohiolink.edu/etdc/view?acc_num=osu1594995213439086 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.
collection	NDLTD
language	English
sources	NDLTD
topic	Biomedical Research Heart valve extracellular matrix heart valve interstitial cells myxomatous degeneration
spellingShingle	Biomedical Research Heart valve extracellular matrix heart valve interstitial cells myxomatous degeneration Dye, Bailey Katherine Cellular Mechanisms of VIC Activation in Mitral Valve Prolapse
author	Dye, Bailey Katherine
author_facet	Dye, Bailey Katherine
author_sort	Dye, Bailey Katherine
title	Cellular Mechanisms of VIC Activation in Mitral Valve Prolapse
title_short	Cellular Mechanisms of VIC Activation in Mitral Valve Prolapse
title_full	Cellular Mechanisms of VIC Activation in Mitral Valve Prolapse
title_fullStr	Cellular Mechanisms of VIC Activation in Mitral Valve Prolapse
title_full_unstemmed	Cellular Mechanisms of VIC Activation in Mitral Valve Prolapse
title_sort	cellular mechanisms of vic activation in mitral valve prolapse
publisher	The Ohio State University / OhioLINK
publishDate	2020
url	http://rave.ohiolink.edu/etdc/view?acc_num=osu1594995213439086
work_keys_str_mv	AT dyebaileykatherine cellularmechanismsofvicactivationinmitralvalveprolapse
_version_	1719457590570647552

Cellular Mechanisms of VIC Activation in Mitral Valve Prolapse

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