Regulation of the fibroblast growth factor-2 axis in cardiac cells, effects on cardioprotection and cardiac muscle cell growth
| dc.contributor.author | Sheikh, Farah | en_US |
| dc.date.accessioned | 2007-05-22T15:16:52Z | |
| dc.date.available | 2007-05-22T15:16:52Z | |
| dc.date.issued | 2001-06-01T00:00:00Z | en_US |
| dc.degree.discipline | Physiology | en_US |
| dc.degree.level | Doctor of Philosophy (Ph.D.) | en_US |
| dc.description.abstract | Cardiovascular disease is the leading cause of death worldwide. Treatments have primarily focussed on the vascular system and shown only moderate 10-20% reductions on major outcomes such as death or myocardial infarction. The research described in this thesis is focussed on developing and testing multiple strategies to regulate cardiac myocyte protection and regeneration in an effort to provide the basis for novel treatments and/or prevention of cardiac disease. MGF-2 is a growth factor that is naturally present in the heart as well as cardiac myocytes and possesses growth promoting and cardioprotective properties, which make it an important therapeutic tool for reducing or preventing damage by ischemia and/or improving cardiac prognosis subsequent to cardiac injury. Although, the protective effects of MGF-2 and the development of exogenous delivery systems are currently being exploited, there has been little effort to exploit these effects by controlling endogenous production of FGF-2. Using gain-of-function transgenics, my research has demonstrated a role for endogenous FGF-2 in the adult heart 'in vivo'. Chronic FGF-2 overexpression was associated with increased "local" FGF-2 release resulting in augmentation of kinases linked with ischemic preconditioning, angiogenesis and cardioprotection. This likely contributed to the increased cardiac myocyte viability observed after ischemia-reperfusion injury in isolated FGF-2 transgenic mouse hearts, representing the first account of the cardioprotective potential of endogenous FGF-2. In addition, my results also demonstrate that endogenous production of FGF-2 can be targeted and is significantly increased in adult mouse cardiac myocytes using the natural catecholamine, norepinephrine. FGF-2 signaling also plays a major role in embryonic and neonatal cardiac myocyte proliferation 'in vitro' and as a result, is implicated in cardiac regeneration. However, the lack of a measurable proliferative response by FGF-2 in the postnatal heart suggested that FGF-2 signaling may be limited and/or antagonized. My results have provided the first indication that levels of the high affinity receptor for FGF-2, FGFR-1, may limit cardiac cell proliferation. Overexpression of FGFR-1 resulted in FGF-2 mediated mitogenic response in FGFR-1 deficient cardiac H9c2 cells as well as primary neonatal cardiac myocytes. This response may involve ERK1/2 MAPK activation and promotion of FGF-2 release. My results also provide direct evidence that transforming growth factor (TGF)-B plays an important role in antagonizing FGF-2 mediated cardiac myocyte entry into the cell cycle. Overexpression of the kinase-deficient TGF-B receptors (TGF-BRII) resulted in serum-induced cardiac myocyte cell cycle entry as well as an amplification of FGF-2 induced S phase entry (13 fold versus 3 fold with FGF-2 alone). Most importantly, these data support a "multiple hit" approach as a therapeutic strategy to stimulate cardiac myocyte proliferation/regeneration following cardiac injury 'in vivo'. In conclusion, my doctoral studies have provided substantial evidence that regulating the FGF-2 axis can be used as a means to exploit the effects of FGF-2 on cardioprotection and cardiac myocyte regeneration in an effort to provide the basis for novel treatments and prevention strategies for cardiac disease. | en_US |
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| dc.format.extent | 184 bytes | |
| dc.format.mimetype | application/pdf | |
| dc.format.mimetype | text/plain | |
| dc.identifier.uri | http://hdl.handle.net/1993/2109 | |
| dc.language.iso | eng | en_US |
| dc.rights | open access | en_US |
| dc.title | Regulation of the fibroblast growth factor-2 axis in cardiac cells, effects on cardioprotection and cardiac muscle cell growth | en_US |
| dc.type | doctoral thesis | en_US |