ROLE OF FIBROBLAST GROWTH FACTOR 2 IN CARDIAC ISCHEMIA-REPERFUSION INJURY AND HYPERTROPHY

ROLE OF FIBROBLAST GROWTH FACTOR 2 IN CARDIAC ISCHEMIA-REPERFUSION INJURY AND HYPERTROPHY

Bibliographic Details
Main Author: HOUSE, STACEY LYNN
Language:English
Published: University of Cincinnati / OhioLINK 2005
Online Access:http://rave.ohiolink.edu/etdc/view?acc_num=ucin1132336027
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spelling ndltd-OhioLink-oai-etd.ohiolink.edu-ucin11323360272021-08-03T06:10:42Z ROLE OF FIBROBLAST GROWTH FACTOR 2 IN CARDIAC ISCHEMIA-REPERFUSION INJURY AND HYPERTROPHY HOUSE, STACEY LYNN Cardiovascular disease is the leading cause of death in the industrialized world. Two of the major etiologies of cardiovascular disease are coronary artery disease resulting in ischemia-reperfusion injury and cardiac hypertrophy leading to myocardial dysfunction and heart failure. Understanding the mechanisms that underly these disease processes may aid in the development of future clinical therapeutics. Growth factors have been implicated in both protection from cardiac ischemia-reperfusion injury and the progression of cardiac hypertrophy. We have utilized mice with a targeted ablation of fibroblast growth factor 2 (Fgf2 knockout) and mice with a cardiac-specific overexpression of FGF2 (FGF2 transgenic) in order to evaluate the role of FGF2 in vivo in both forms of cardiac pathology. When subjected to an isolated work-performing heart model of global low-flow ischemia-reperfusion injury, Fgf2 knockout hearts have significantly increased myocardial dysfunction compared to wildtype hearts. FGF2 transgenic hearts, however, have significantly improved post-ischemic recovery of contractile function and smaller infarcts. Pharmacological inhibition of signal transduction cascades reveal that the cardioprotective effect of FGF2 overexpression is mediated through the activation of the mitogen activated protein kinase, ERK, activation of the protein kinase C (PKC) pathway, activation of nitric oxide synthases, and inhibition of the stress activated protein kinase, p38. To ascertain the role of FGF2 in cardiac hypertrophy, wildytpe, Fgf2 knockout, non-transgenic, and FGF2 transgenic mice were treated with isoproterenol via subcutaneous mini-osmotic pump implants to induce a hypertrophic response. Fgf2 knockout hearts are protected from isoproterenol-induced cardiac hypertrophy; whereas, FGF2 transgenic hearts show an exacerbated cardiac hypertrophic repsonse. Echocardiography reveals significantly decreased fractional shortening in isoproterenol-treated FGF2 transgenic mice but not in Fgf2 knockout mice suggesting that FGF2 mediates the maladaptive cardiac dysfunction seen in cardiac hypertrophy induced by isoproterenol. Pharmacological inhibition of ERK or p38 signaling revealed that FGF2 activation of ERK but not p38 is necessary to FGF2’s role in the mediation of cardiac hypertrophy. Together these data show that, in vivo, FGF2 can have both beneficial and deleterious effects in the heart by protecting the myocardium from ischemia-reperfusion injury and mediating isoproterenol-induced cardiac hypertrophy and that multiple signaling cascades mediate these differential effects. 2005 English text University of Cincinnati / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=ucin1132336027 http://rave.ohiolink.edu/etdc/view?acc_num=ucin1132336027 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.
collection NDLTD
language English
sources NDLTD
author HOUSE, STACEY LYNN
spellingShingle HOUSE, STACEY LYNN
ROLE OF FIBROBLAST GROWTH FACTOR 2 IN CARDIAC ISCHEMIA-REPERFUSION INJURY AND HYPERTROPHY
author_facet HOUSE, STACEY LYNN
author_sort HOUSE, STACEY LYNN
title ROLE OF FIBROBLAST GROWTH FACTOR 2 IN CARDIAC ISCHEMIA-REPERFUSION INJURY AND HYPERTROPHY
title_short ROLE OF FIBROBLAST GROWTH FACTOR 2 IN CARDIAC ISCHEMIA-REPERFUSION INJURY AND HYPERTROPHY
title_full ROLE OF FIBROBLAST GROWTH FACTOR 2 IN CARDIAC ISCHEMIA-REPERFUSION INJURY AND HYPERTROPHY
title_fullStr ROLE OF FIBROBLAST GROWTH FACTOR 2 IN CARDIAC ISCHEMIA-REPERFUSION INJURY AND HYPERTROPHY
title_full_unstemmed ROLE OF FIBROBLAST GROWTH FACTOR 2 IN CARDIAC ISCHEMIA-REPERFUSION INJURY AND HYPERTROPHY
title_sort role of fibroblast growth factor 2 in cardiac ischemia-reperfusion injury and hypertrophy
publisher University of Cincinnati / OhioLINK
publishDate 2005
url http://rave.ohiolink.edu/etdc/view?acc_num=ucin1132336027
work_keys_str_mv AT housestaceylynn roleoffibroblastgrowthfactor2incardiacischemiareperfusioninjuryandhypertrophy
_version_ 1719432237631406080

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