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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

View larger version (62K): [in a new window]   Figure 1 Left ventricular tissue of fibroblast growth factor-1 (FGF-1) transgenic and wild-type mice was stained with polyclonal antibody against FGF-1 (Promega, Madison, Wisconsin), and Vector red was applied as the secondary antibody. The diffuse staining of cardiomyocytes and extracellular matrix was observed in FGF-1 transgenic mice. Negative control shows background staining with only the secondary antibody Vector red. Note the low expression level of FGF-1 in the non-transgenic littermates.

View larger version (32K): [in a new window]   Figure 2 Cardiac function and cardiac functional recovery after global ischemia and reperfusion in fibroblast growth factor (FGF) and wild-type (WT) control hearts: (A) Aortic flow in ml/min. (B) Left ventricular developed pressure in mm Hg. (C) Maximal rate of positive pressure development (dP/dtmax in mm Hg/s2). (D) Left ventricular diastolic pressure (in mm Hg). *p < 0.05 compared with WT. "Basal" indicates the pre-ischemic period, "L" indicates Langendorff reperfusion, and "+15, +25, +35, +60 min" indicate 15, 25, 35, and 60 min of antegrade reperfusion, respectively.

View larger version (21K): [in a new window]   Figure 3 Pre- and post-ischemic lactate dehydrogenase (LDH) (A) and lactate (B) release in fibroblast growth factor (FGF) and wild-type (WT) control hearts (lactate in µmol/l·min and LDH in U/l; *p < 0.05 compared with WT). "Basal" indicates the pre-ischemic period, "L" indicates Langendorff reperfusion, and "+15, +25, +35, +60 min." indicates 15, 25, 35, and 60 min of antegrade reperfusion, respectively.

View larger version (51K): [in a new window]   Figure 4 Western blot analysis demonstrating the activation of mitogen-activated protein kinases (MAPKs) (ERK-1/2, JNK-1/2, p38) and protein kinase C (PKC)- translocation to the particulate fraction. Each lane was loaded with equal amounts of protein. Polyclonal antibodies were used to detect bands. The upper panel of each figure is a representative blot, whereas the lower panels depict grouped densitometric data (mean ± SEM) from three experiments. For MAPKs, we used the ratio of phosphorylated MAPK/non-phosphorylated MAPK. (A) The upper panel shows a representative blot of the amount of PKC- translocation to the particulate fraction, whereas the lower panel demonstrates the quantitative densitometric data of PKC- translocation to the particulate fraction. (B to D) The upper panels show a representative blot of the activated form of each MAPK subtype, whereas the lower panel depicts the quantification of densitometric data. (B) phospho-ERK, (C) phospho-JNK1/2, (D) phospho-p38. CHE = chelerythrine; FGF = fibroblast growth factor transgenic littermates; IR = ischemia and reperfusion; LA = lavendustin A; PKC = protein kinase C; WT = wild-type littermates.

View larger version (33K): [in a new window]   Figure 5 Cardiac functional recovery in untreated fibroblast growth factor (FGF) and wild-type (WT) control hearts. In addition, this figure demonstrates the hemodynamic effects of pretreatment of FGF hearts with selective inhibitors of tyrosine kinases (FGF/LA), PKC (FGF/CHE), and FGF-R1 (FGF/SU). (A) Aortic flow. (B) Left ventricular developed pressure. (C) Maximal rate of positive pressure development (dP/dtmax in mm Hg/s2). (D) Left ventricular diastolic pressure. *p < 0.05 compared with WT, p < 0.05 compared with FGF. Che = chelerythrine chloride; LA = lavendustin A; SU = SU5402. "Basal" indicates the preischemic period, "L" indicates Langendorff reperfusion, and "+15, +25, +35, +60 min" indicates 15, 25, 35, and 60 min of antegrade reperfusion, respectively.

View larger version (17K): [in a new window]   Figure 6 Pre- and post-ischemic lactate dehydrogenase (LDH) release in non-treated and inhibitor-treated fibroblast growth factor (FGF) hearts and wild-type (WT) control hearts. LDH release in U/l (*p < 0.05 compared with WT, p < 0.05 compared with FGF). CHE = chelerythrine; LA = lavendustin A; SU = SU5402. Open bars = pre-ischemia; closed bars = post-ischemia.