The overall goal of this proposal is to investigate the molecular target(s) underlying FGF2-mediated cardioprotection. Findings from the original proposal indicate that nitric oxide (NO), protein kinase C (PKC), and mitogen-activated protein kinase (MAPK) signaling are necessary for FGF2-induced cardioprotection. Yet, the downstream targets by which these signaling pathways mediate FGF2- induced cardioprotection against myocardial dysfunction and infarction remain to be elucidated. Therefore, we will undertake a pharmacological-, electrophysiological-, subproteomic- and integrative physiological-based multidisciplinary approach to identify known or novel substrates of the signaling pathways associated with FGF2-induced cardioprotection. The proposal will evaluate the involvement of known downstream substrates of kinases that have been affiliated with FGF2 activity or with cardioprotection, and identify novel targets of FGF2-induced cardioprotection by subproteomic analysis. The research plan will integrate basic information at the protein and cellular level with information at the whole organ/animal level. These studies will also enable us to directly relate changes in myocardial infarction and post-ischemic recovery of ventricular function to the biological activity of FGF2 and to specific downstream targets of its protein kinase pathways. To ascertain the involvement of ATP-sensitive potassium (KATP) channels in FGF2-induced cardioprotection, we will employ pharmacologic, electrophysiological, and molecular methods. Similar techniques will be used to determine the importance of FGF2 in regulating calcium homeostasis at the level of sarco(endo)plasmic reticulum (SR) proteins and contractile apparatus, ultimately influencing post- ischemic cardiac function. With preliminary data implicating the mitochondria, SR, and contractile apparatus as targets of FGF2-induced cardioprotection, candidate and novel substrates of these organelles will be interrogated via phosphoproteomic (immunoblotting and 2-D gel/MS) techniques. Results of this proposal will provide new insights into FGF2-induced cardioprotection and may eventually lead to the pharmacologic or genetic development of FGF2 as a therapy against ischemic heart disease.

Public Health Relevance

Cardiovascular disease is the primary cause of death in the United States. Understanding the molecular and cellular basis of cardioprotection is a necessary step towards developing FGF2 as a therapeutic strategy to limit the extent of acute myocardial infarction and protect the heart in the clinical setting.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL075633-08
Application #
8496517
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Schwartz, Lisa
Project Start
2003-11-01
Project End
2015-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
8
Fiscal Year
2013
Total Cost
$404,985
Indirect Cost
$147,033
Name
University of Cincinnati
Department
Pharmacology
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
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
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; 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
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
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
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 S; Liao, Siyun; Gross, Garrett J et al. (2007) Remote preconditioning-endocrine factors in organ protection against ischemic injury. Endocr Metab Immune Disord Drug Targets 7:167-75
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
Liao, Siyun; Porter, Darius; Scott, Alana et al. (2007) The cardioprotective effect of the low molecular weight isoform of fibroblast growth factor-2: the role of JNK signaling. J Mol Cell Cardiol 42:106-20

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