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Wnt/ß-catenin signaling pathway in non-myocyte lineages in the heart

Fang, Ming
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1458299605

Abstract Details

2016, PhD, University of Cincinnati, Medicine: Molecular and Developmental Biology.
Cardiovascular disease is the leading cause of death in adults in the United States and worldwide. Myxomatous valve disease (MVD) is the second most common heart valve disease in human, and excessive proteoglycan accumulation along with degradation of collagen fibers is the characteristic of MVD. Faulty myxomatous heart valves result in valvular regurgitation and prolapse leading to insufficient blood supply to the periphery, thus compromising cardiac function. Cardiac fibrosis is a common feature in heart failure. Chronic fibrotic response in the injured heart results in increased production of fibrillar collagens and formation of stiff collagen fibers, which can reduce myocardial compliance and disrupt cardiac conduction, and therefore it further contributes to the progression of heart failure. Valvular interstitial cells (VICs) and cardiac fibroblasts (CFs) are two distinct collagen-producing non-myocyte lineages that contribute to MVD and cardiac fibrosis, respectively. Although Wnt/ß-catenin is required for developmental epithelial/endothelial-to-mesenchymal transition (EMT) in the formation of VICs and CFs, its roles in their extracellular matrix (ECM) homeostasis and remodeling are not known, and its relations to MVD or cardiac fibrosis are not well defined. In Chapter 2, we show that Wnt/ß-catenin signaling inhibits Sox9 nuclear localization and proteoglycan expression in cultured chicken embryo aortic valves. VIC-specific loss of ß-catenin (Ctnnb1 fl/fl) driven by PostnCre in mice leads to the formation of aberrant chondrogenic nodules and induction of chondrogenic gene expression in adult aortic valves (AoVs). These nodular cells strongly express nuclear Sox9 and Sox9 downstream chondrogenic extracellular matrix genes, including Aggrecan, Col2a1, and Col10a1. Excessive chondrogenic proteoglycan accumulation and disruption of stratified ECM maintenance in the AoV leaflets are characteristics of MVD. Therefore, ß-catenin limits Sox9 nuclear localization and inhibits chondrogenic differentiation during valve development and in adult aortic valve homeostasis. In Chapter 3, we have demonstrated that Wnt/ß-catenin signaling in CFs is required for collagen gene expression after trans-aortic constriction (TAC)-induced pressure overload in mice. Loss of ß-catenin in TCF21MerCreMer or PostnMerCreMer lineage significantly improves cardiac function, suppresses cardiac fibrosis and reduces expression of Col1a1, Col3a1 and Tgfß2. However, loss of ß-catenin in the TCF21 MerCreMer lineage does not decrease the number of α-SMA+ cells or the number of α-Vimentin+;Endomucin- CFs, indicating that CF activation is not affected. Our data also suggest that cardiac fibrosis and cardiac hypertrophy are interconnected, and Wnt/ß-catenin in CFs plays an important and integral role for both fibrosis and indirectly cardiomyocyte hypertrophy. Together these studies demonstrate that Wnt/ß-catenin plays essential roles in regulation of normal ECM homeostasis in VICs and collagen gene expression in CFs after pressure overload in mice.
Katherine Yutzey, Ph.D. (Committee Chair)
Burns Blaxall, Ph.D. (Committee Member)
Rulang Jiang, Ph.D. (Committee Member)
Jason Shearn, Ph.D. (Committee Member)
Aaron Zorn, Ph.D. (Committee Member)
246 p.
Developmental Biology
Wnt signaling pathway; heart valve disease; cardiac fibrosis; non-myocyte lineages; proteoglycans; collagens

Recommended Citations

Citations

  • Fang, M. (2016). Wnt/ß-catenin signaling pathway in non-myocyte lineages in the heart [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1458299605

    APA Style (7th edition)

  • Fang, Ming. Wnt/ß-catenin signaling pathway in non-myocyte lineages in the heart. 2016. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1458299605.

    MLA Style (8th edition)

  • Fang, Ming. "Wnt/ß-catenin signaling pathway in non-myocyte lineages in the heart." Doctoral dissertation, University of Cincinnati, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1458299605

    Chicago Manual of Style (17th edition)

ucin1458299605
143
© 2016, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.