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Signaling mechanisms controlling the proliferation and differentiation of cardiac fibroblasts

Olson, Erik Ryan
http://rave.ohiolink.edu/etdc/view?acc_num=kent1162230649

Abstract Details

2006, PHD, Kent State University, College of Biomedical Sciences.
Cardiac fibroblasts (CFs) are the major non-contractile cells present in the myocardium. The primary responsibility of CFs is to regulate the synthesis and secretion of extracellular matrix (ECM) proteins. Excessive proliferation and differentiation of CFs during cardiovascular pathologies directly leads to the development of cardiac fibrosis, a condition characterized by a stiffening of the myocardium, which has significant effects on cardiac function. Resveratrol (RES), a component of red wine, has been identified as an agent having considerable cardioprotective properties. The first Specific Aim of my dissertation research was designed to investigate the effects of RES on CF function. I concluded that 25 microM RES significantly inhibited CF proliferation and myofibroblast differentiation, thus identifying RES as a potential anti-fibrotic agent. A common characteristic of cardiovascular diseases is the activation of the renin-angiotensin system, resulting in increased circulating angiotensin II (ANG II). ANG II directly stimulates CF proliferation, myofibroblast differentiation, and de novo synthesis of collagens and other ECM proteins and therefore, an elevation in systemic ANG II is a major contributing factor in the progression of cardiac fibrosis. The intracellular signaling pathways mediating the effects ANG II signaling are most well characterized in vascular smooth muscle cells (VSMCs). Proliferation of CFs by ANG II is dependent on the ERK 1/2 signaling pathway, but the exact pathway from the ANG II type 1 receptor to ERK 1/2 has not yet been elucidated in adult CFs. Through studies outlined in the second Aim, I determined that ANG II-induced ERK 1/2 activation is dependent on both intracellular calcium and protein kinase C (PKC). I also concluded that ANG II stimulation did not induce transactivation of the epidermal growth factor receptor, a finding which distinguishes ANG II signaling in adult CFs from that in neonatal CFs and VSMCs. In addition, I determined that ANG II did not signal to ERK 1/2 through a phosphatidylinositol 3-kinase (PI3-K) and atypical PKCzeta, another distinguishing feature of ANG II signaling in adult CFs. I did, however, conclude that cellular proliferation was dependent on active PI3-K and PKCzeta, and that prolonged PKCzeta inhibition resulted in DNA fragmentation and cytoskeletal degradation, indicating that the cells were undergoing apoptosis. The third Aim was designed to explore whether or not alpha-adrenergic receptor (alpha-AR) signaling had a role in myofibroblast differentiation. I first found that the expected effects of selective alpha1-AR stimulation with phenylephrine (PHE) were lacking in adult CFs, including inositol phosphate production and intracellular calcium release. Second, there was no increase in myofibroblast differentiation in response to PHE. Lastly, PHE appeared to increase ERK 1/2 activation, but this effect was not blocked by a specific antagonist of the alpha1-AR. Therefore, I concluded that alpha-ARs are not involved in myofibroblast differentiation. The information gained from this project was that resveratrol has potential anti-fibrotic properties and that angiotensin II signaling pathways mediating proliferation of adult cardiac fibroblasts differ considerably from those identified in neonatal CFs and VSMCs.
J Meszaros (Advisor)
168 p.
Biology, Cell
cardiac fibroblast; angiotensin II; fibrosis; MAPK

Recommended Citations

Citations

  • Olson, E. R. (2006). Signaling mechanisms controlling the proliferation and differentiation of cardiac fibroblasts [Doctoral dissertation, Kent State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=kent1162230649

    APA Style (7th edition)

  • Olson, Erik. Signaling mechanisms controlling the proliferation and differentiation of cardiac fibroblasts. 2006. Kent State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=kent1162230649.

    MLA Style (8th edition)

  • Olson, Erik. "Signaling mechanisms controlling the proliferation and differentiation of cardiac fibroblasts." Doctoral dissertation, Kent State University, 2006. http://rave.ohiolink.edu/etdc/view?acc_num=kent1162230649

    Chicago Manual of Style (17th edition)

kent1162230649
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© 2006, all rights reserved.
This open access ETD is published by Kent State University and OhioLINK.
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