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Fibroblast growth factor 2-mediated cardioprotection: the kinase mediators and downstream targets of FGF2-induced protection from ischemia and reperfusion injury

Manning, Janet R.
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1331296684

Abstract Details

2012, PhD, University of Cincinnati, Medicine: Molecular, Cellular and Biochemical Pharmacology.
Although heart disease is the primary cause of death in several industrialized nations, there are no widely-used therapies targeting the ischemic heart muscle; current therapies focus on rapid restoration of blood flow, which produces its own set of injuries. Fibroblast growth factor 2 (FGF2) has been shown to protect the heart from ischemia and reperfusion (I/R) injury, reducing infarct size and postischemic dysfunction. However, it is unclear by what mechanism the two classes of FGF2 expressed in the cardiomyocyte, high molecular weight (HMW) FGF2, and low molecular weight (LMW) FGF2, exert protective action on the ischemic heart. It has been established that LMW FGF2 protects the heart from postischemic dysfunction, while endogenously expressed HMW FGF2 reduces contractile function and relaxation after I/R injury. The mechanisms by which this occurs are not well understood. The purpose of this dissertation was to investigate the mechanisms of these differential effects, including elucidating the role of a known cardioprotective kinase, protein kinase C (PKC), in the signal transduction pathways initiated by FGF2 isoforms, as well as the downstream targets of this and other kinases. Of particular interest was determining which isoforms of PKC are mediating LMW FGF2-induced protection from I/R injury, and investigating known and novel targets of these PKC isoforms at the myofibril and sarcoplasmic reticulum that may modulate contractile function. Using mice that only express the LMW FGF2 isoform, it was determined that LMW FGF2 differentially activates PKCe and a, and that these isoforms of PKC were necessary for LMW FGF2-mediated protection. Expression of only LMW FGF2 was also found to increase troponin I and T phosphorylation during ischemia, as well as the activity of actomyosin ATPase, in a manner that was dependent on PKCa. ATPase. Additionally, differences in calcium cycling were seen in hearts only expressing LMW FGF2, although no changes in basal levels of calcium cycling proteins were observed. However, a significant elevation of phosphorylated pThr-17 phospholamban was seen at early ischemia, suggesting that this phosphorylation may play a role in LMW FGF2 mediated protection from postischemic dysfunction. Also of interest is the mechanism by which HMW FGF2 reduces postischemic function. It was hypothesized that HMW FGF2 produces its detrimental effects by interfering with protective LMW FGF2 signaling. It was found that after I/R injury, the HMW FGF2 overexpresion results in lowered FGF receptor 1 (FGFR1) activation, which is necessary for LMW FGF2-mediated protection, as well as lowered activity of downstream kinases of FGFR1. Finally, novel targets of both HMW and LMW FGF2 were investigated. It was found using pharmacological methodologies that overexpression of HMW and LMW FGF2 result in a PKC- and MAPK-dependent increase in nitric oxide (NO) production, suggesting that NO synthase (NOS) is a target of FGF2 signaling. In addition, it was found using a microarray that HMW and LMW differentially regulate the expression of genes that may play a potentially protective role in I/R injury. These results elucidate a novel mechanism for a potentially therapeutic molecule to protect the heart from ischemia and reperfusion injury.
Jo El Schultz, PhD (Committee Chair)
Walter Jones, PhD (Committee Member)
Terence Kirley, PhD (Committee Member)
Evangelia Kranias, PhD (Committee Member)
Mohammed Matlib, PhD (Committee Member)
Jeff Molkentin, PhD (Committee Member)
267 p.
Pharmacology
FGF2; heart; ischemia; PKC; contractile dysfunction; myofibril;

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Citations

  • Manning, J. R. (2012). Fibroblast growth factor 2-mediated cardioprotection: the kinase mediators and downstream targets of FGF2-induced protection from ischemia and reperfusion injury [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1331296684

    APA Style (7th edition)

  • Manning, Janet. Fibroblast growth factor 2-mediated cardioprotection: the kinase mediators and downstream targets of FGF2-induced protection from ischemia and reperfusion injury. 2012. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1331296684.

    MLA Style (8th edition)

  • Manning, Janet. "Fibroblast growth factor 2-mediated cardioprotection: the kinase mediators and downstream targets of FGF2-induced protection from ischemia and reperfusion injury." Doctoral dissertation, University of Cincinnati, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1331296684

    Chicago Manual of Style (17th edition)

ucin1331296684
865
© 2012, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.