The overall objective of this proposal is to investigate the signaling mechanisms underlying the cardioprotective effect of fibroblast growth factor-2 (FGF2). The pathway(s) triggered by FGF2 to elicit protection in the heart during ischemia is unknown. However, evidence indicates that in many cell types, FGF2 can signal through protein kinase C (PKC), mitogen-activated protein kinase (MAPK), or nitric oxide (NO) and ATP-sensitive potassium (KATP) channels to mediate certain biological functions including cellular growth, vasodilation, and angiogenesis. All of these signaling pathways have also been shown to be important in cardioprotection. A broad multidisciplinary approach will be established that will combine diverse techniques (integrative physiology, molecular genetics, gene-targeted/transgenic mouse models, and pharmacology) and will integrate genetic information at the molecular level with physiological information at the whole organ/animal level. To ascertain the molecular mechanism(s) for FGF2-mediated cardioprotection, we will assess the patterns in activity of protein kinases (PKC and MAPK) that are either known to mediate FGF2 signaling or have been implicated in the development of cardioprotection. This will be done by determining which of these pathways is markedly altered prior to and during ischemia-reperfusion injury in wildtype and FGF2 transgenic mouse hearts and correlating these molecular/biochemical changes with post ischemic recovery of cardiac function and myocardial infarction. The effects of chronic cardiac expression of FGF2 upon nitric oxide synthase (NOS) mRNA, protein, enzymatic activity, and cellular distribution will be systematically defined for all three isoforms (eNOS, iNOS, and nNOS), providing for the first time a thorough characterization of these changes in the mouse heart. Furthermore, the effect of pharmacological inhibitors of PKC, MAPK, NOS, and KATP channels, on post-ischemic recovery of cardiac function and infarct size will be investigated and correlated with the biological actions of FGF2. Integration of these signaling pathways will be evaluted to determine whether activation occurs in a parallel or serial fashion to modulate FGF2-induced cardioprotection. The results from this proposal will provide important new insights into molecular and signaling mechanisms of FGF2-induced cardioprotection and should facilitate the development of novel pharmacological and/or gene therapeutic strategies that improve and enhance cardiac resistance to ischemia in susceptible cardiac patients. ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL075633-01A1
Application #
6822386
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Wang, Lan-Hsiang
Project Start
2004-07-01
Project End
2008-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
1
Fiscal Year
2004
Total Cost
$378,828
Indirect Cost
Name
University of Cincinnati
Department
Pharmacology
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Huang, Chahua; Liu, Yang; Beenken, Andrew et al. (2017) A novel fibroblast growth factor-1 ligand with reduced heparin binding protects the heart against ischemia-reperfusion injury in the presence of heparin co-administration. Cardiovasc Res 113:1585-1602
Wijeratne, Aruna B; Manning, Janet R; Schultz, Jo El J et al. (2013) Quantitative phosphoproteomics using acetone-based peptide labeling: method evaluation and application to a cardiac ischemia/reperfusion model. J Proteome Res 12:4268-79
Manning, Janet R; Perkins, Sarah O; Sinclair, Elizabeth A et al. (2013) Low molecular weight fibroblast growth factor-2 signals via protein kinase C and myofibrillar proteins to protect against postischemic cardiac dysfunction. Am J Physiol Heart Circ Physiol 304:H1382-96
Manning, Janet R; Carpenter, Gregory; Porter, Darius R et al. (2012) Fibroblast growth factor-2-induced cardioprotection against myocardial infarction occurs via the interplay between nitric oxide, protein kinase signaling, and ATP-sensitive potassium channels. Growth Factors 30:124-39
Liao, Siyun; Bodmer, Janet R; Azhar, Mohamad et al. (2010) The influence of FGF2 high molecular weight (HMW) isoforms in the development of cardiac ischemia-reperfusion injury. J Mol Cell Cardiol 48:1245-54
Azhar, Mohamad; Runyan, Raymond B; Gard, Connie et al. (2009) Ligand-specific function of transforming growth factor beta in epithelial-mesenchymal transition in heart development. Dev Dyn 238:431-42
Bolte, Craig; Newman, Gilbert; Schultz, Jo El J (2009) Hypertensive state, independent of hypertrophy, exhibits an attenuated decrease in systolic function on cardiac kappa-opioid receptor stimulation. Am J Physiol Heart Circ Physiol 296:H967-75
Liao, Siyun; Bodmer, Janet; Pietras, Daniel et al. (2009) Biological functions of the low and high molecular weight protein isoforms of fibroblast growth factor-2 in cardiovascular development and disease. Dev Dyn 238:249-64
Bolte, Craig; Newman, Gilbert; Schultz, Jo El J (2009) Kappa and delta opioid receptor signaling is augmented in the failing heart. J Mol Cell Cardiol 47:493-503
House, Stacey L; Melhorn, Susan J; Newman, Gilbert et al. (2007) The protein kinase C pathway mediates cardioprotection induced by cardiac-specific overexpression of fibroblast growth factor-2. Am J Physiol Heart Circ Physiol 293:H354-65

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