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The impact of the extracellular matrix and type 1 diabetes on cardiac fibroblast activation

Shamhart, Patricia E.
http://rave.ohiolink.edu/etdc/view?acc_num=kent1283881511

Abstract Details

2010, PHD, Kent State University, College of Arts and Sciences / School of Biomedical Sciences.
Cardiac fibroblasts (CFs) are the major non-contractile cells present in the myocardium and are the primary producers of the extracellular matrix (ECM) in the heart. Cardiac fibrosis, an accumulation of ECM, is often the result of overactive fibroblasts. Cardiac fibroblasts are activated by numerous stimuli including ECM components, circulating hormones such as angiotensin II (ANG II), and hyperglycemia. Excessive proliferation, migration, and differentiation of fibroblasts contribute to the fibrosis, and therefore it is crucial to study the mechanisms that regulate these processes to unveil new targets aimed at preventing prolonged fibroblast activation and fibrosis. The overall goal of this project is to understand how the ECM, ANG II, and diabetes affect cardiac fibroblast activation. To achieve this goal, Aim 1 will determine the influence of collagen types I, III, VI on fibroblast and myofibroblast migration. Aim 2 will establish the specific PKC isoform mediating angiotensin II-induced ERK 1/2 phosphorylation. Aim 3 is designed to explore how hyperglycemia alters cardiac fibroblast proliferation, migration, myofibroblast differentiation and whether changes in ECM composition can alter the function of cardiac fibroblasts in high glucose media. Finally, Aim 4 will determine the influence of type 1 diabetes on fibroblast activation in the in vivo setting. This dissertation reveals that type III collagen and to a lesser extent, type I collagen promote migration whereas fibroblasts and myofibroblasts plated on collagen VI exhibit delayed migration. This study demonstrates that ANG II stimulates ERK1/2 phosphorylation via activation of distinct parallel signaling pathways mechanistically controlled by intracellular Ca2+ and PKC delta. This study also reveals that hyperglycemia induces CF proliferation and accelerates myofibroblast differentiation in vitro and that early stage diabetic hearts contain highly proliferative fibroblasts, but have significantly fewer myofibroblasts. Since diabetic patients develop cardiovascular complications including fibrosis and are less likely to survive a myocardial infarction, we speculate that this is due to deficits in their wound healing capabilities caused by the low number of myofibroblasts. Targeting the mechanisms regulating cardiac fibroblast activity to prevent overactivation, or in the case of diabetes, to replenish myofibroblasts, may lead to new therapies to combat the progression of heart disease and cardiac fibrosis.
J. Gary Meszaros, PhD (Committee Chair)
Ian Bratz, PhD (Committee Member)
Derek Damron, PhD (Committee Member)
Daniel Ely, PhD (Committee Member)
Bansidhar Datta, PhD (Committee Member)
165 p.
Biomedical Research; Cellular Biology
cardiac fibroblast; diabetes; angiotenin II; myofibroblast

Recommended Citations

Citations

  • Shamhart, P. E. (2010). The impact of the extracellular matrix and type 1 diabetes on cardiac fibroblast activation [Doctoral dissertation, Kent State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=kent1283881511

    APA Style (7th edition)

  • Shamhart, Patricia. The impact of the extracellular matrix and type 1 diabetes on cardiac fibroblast activation. 2010. Kent State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=kent1283881511.

    MLA Style (8th edition)

  • Shamhart, Patricia. "The impact of the extracellular matrix and type 1 diabetes on cardiac fibroblast activation." Doctoral dissertation, Kent State University, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=kent1283881511

    Chicago Manual of Style (17th edition)

kent1283881511
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© 2010, all rights reserved.
This open access ETD is published by Kent State University and OhioLINK.
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