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Fibroblast growth factor-1 improves cardiac functional recovery and enhances cell survival after ischemia and reperfusion

A fibroblast growth factor receptor, protein kinase c, and tyrosine kinase-dependent mechanism

Meindert Palmen, MD, PhD^*, Mat J.A.P. Daemen, MD, PhD, Leon J. De Windt, PhD^*, Jodil Willems, Willem R.M. Dassen, PhD^*, Sylvia Heeneman, PhD, Rene Zimmermann, PhD, Marc Van Bilsen, PhD and Pieter A. Doevendans, MD, PhD^||,¶,*

^* Department of Cardiology
Department of Pathology
Department of Physiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht, the Netherlands
Department of Vascular Genomics, Bad Nauheim, Germany
^|| Interuniversity Cardiology Institute Netherlands
^¶ Heart Lung Center Utrecht (HLCU), Utrecht, the Netherlands

Manuscript received December 12, 2002; revised manuscript received March 1, 2004, accepted May 4, 2004.

^* Reprint requests and correspondence: Dr. Pieter. A. Doevendans, Heart and Lung Center Utrecht (HLCU), University Hospital Utrecht, Department of Cardiology (room HP E 03.406), 3584CX Utrecht, The Netherlands (Email: p.doevendans{at}hli.azu.nl).

OBJECTIVES: We sought to investigate the role of fibroblast growth factor (FGF)-1 during acute myocardial ischemia and reperfusion.

BACKGROUND: The FGFs display cardioprotective effects during ischemia and reperfusion.

METHODS: We investigated FGF-1–induced cardioprotection during ischemia and reperfusion and the intracellular signaling pathways responsible for these effects in an ex vivo murine setup of myocardial ischemia and reperfusion.

RESULTS: Cardiac-specific human FGF-1 overexpression was associated with enhanced post-ischemic hemodynamic recovery and decreased lactate dehydrogenase release during reperfusion. Inhibition of the FGF receptor, protein kinase C (PKC), and tyrosine kinase (TK) resulted in blockade of FGF-1-induced protective effects on cardiac functional recovery and cell death.

CONCLUSIONS: The overexpression of FGF-1 induces cardioprotection through a pathway that involves the FGF receptor, PKC, and TK.

Abbreviations and Acronyms   AOF = aortic flow   DMSO = dimethyl sulfoxide   dP/dtmax = maximal rate of positive pressure development (in mm Hg/s2)   dP/dtmin = minimal rate of negative pressure development (in mm Hg2)   FGF = fibroblast growth factor   HW/BW = heart weight/body weight   IPC = ischemic preconditioning   I/R = ischemia and reperfusion   LDH = lactic dehydrogenase   LVDP = left ventricular developed pressure   LVEDP = left ventricular end diastolic pressure   LVPdia = diastolic left ventricular pressure   LVPsys = systolic left ventricular pressure   MAPK = mitogen-activated protein kinase   PKC = protein kinase C   TG = transgenic   TK = tyrosine kinase   WT = wild type

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