Washington University School of Medicine Digital Commons@Becker Conference Abstracts and Posters Division of Emergency Medicine/Emergency Care Research Section 2011 Cardioprotection by endogenous fibroblast growth factor 2 in cardiac ischemia-reperfusion injury in vivo Stacey House Washington University School of Medicine in St. Louis Carla Weinheimer Washington University School of Medicine in St. Louis Attila Kovacs Washington University School of Medicine in St. Louis David Ornitz Washington University School of Medicine in St. Louis Follow this and additional works at: http://digitalcommons.wustl.edu/em_conf Recommended Citation House, Stacey; Weinheimer, Carla; Kovacs, Attila; Ornitz, David, Cardioprotection by endogenous fibroblast growth factor 2 in cardiac ischemia-reperfusion injury in vivo (2011). Conference Abstracts and Posters. Paper 7. http://digitalcommons.wustl.edu/ em_conf/7 This Presentation Paper is brought to you for free and open access by the Division of Emergency Medicine/Emergency Care Research Section at Digital Commons@Becker. It has been accepted for inclusion in Conference Abstracts and Posters by an authorized administrator of Digital Commons@Becker. For more information, please contact engeszer@wustl.edu.
Cardioprotection by Endogenous Fibroblast Growth Factor 2 in Cardiac Ischemia- Reperfusion Injury In Vivo Stacey House MD PhD, Carla Weinheimer MS, Attila Kovacs MD, and David Ornitz MD PhD Washington University in St. Louis School of Medicine Society for Academic Emergency Medicine Great Plains Regional Research Forum St. Louis, MO. September 2011 Stacey House, 2011
Fibroblast Growth Factor 2 22 different FGF family members (10 in heart) FGF2 or basic FGF first member of the FGF family identified, expressed fairly ubiquitously FGF2 expressed in all developmental stages of heart; found in cardiomyocytes, fibroblasts, endothelium FGF2 known functions: Hematopoiesis Angiogenesis Wound Healing Mesoderm Induction Cell Survival/Death Cardiac Hypertrophy
FGF2 Isoforms FGF2 mrna (1) (484) (951) 5 AUG (486) CUG (86) CUG (319) CUG (346) CUG (361) Stop(951) 3 HMW LMW 34 kda 24 kda 22.5 kda 22 kda 18 kda nuclear cytoplasmic Nuclear localization signal
FGF2 and Cardioprotection Isolated work-performing global low-flow IR injury- Fgf2 KO have worsened post-ischemic function Cardiac-specific human FGF2 Tg have -improved post-ischemic cardiac function -reduced infarct size FGF2-induced cardioprotection mediated through PKC, MAPK, and NOS signaling
What is the in vivo cardioprotective efficacy of FGF2?
FGF2 Knockout Targeted ablation of all isoforms of FGF2 Viable and fertile No difference from wildtype with respect to cardiac morphometry, function, or vessel density
Closed Chest Ischemia-Reperfusion Instrumentation 90 min Ischemia 7 Days 7 Days Reperfusion Echo Day 1 Echo Day 7 From Dewald et al. 2004
Echo Determination of Ejection Fraction
Endogenous FGF2 in Cardiac Function Post IR Injury 80 Wildtype 70 FGF2 KO Ejection Fraction % 60 50 40 30 20 * * 10 0 1 day 7 day n=6 *p<0.05 vs. wildtype
Echo Analysis of LV Wall Motion Abnormalities
Echo Analysis of LV Wall Motion Abnormalities 50 Wildtype 45 40 * * FGF2 KO % Infarct Size 35 30 25 20 15 10 5 0 1 day 7 day n=6 *p<0.05 vs. wildtype
Trichrome Staining of Fibrosis Wildtype Fgf2 KO
Picosirius Red Stain of Collagen Fibrils
Endogenous FGF2 Effect on Cardiac Hypertrophy Heart Wt vs. Body Wt Ratio 0.01 0.009 0.008 0.007 0.006 0.005 0.004 0.003 0.002 Wildtype FGF2 KO 0.001 0 Heart Wt vs. Body Weight Ratio n=7
Myocyte Area Staining Wildtype Fgf2 KO
Myocyte Cross Sectional Area Post IR Injury Myocyte Cross Sectional Area (um 2 ) 400 350 300 250 200 150 100 50 0 Wildtype Fgf2 KO n=6
Smooth Muscle Actin Staining Wildtype Fgf2 KO
Vessel Density After IR injury SMA (# vessels/10x field) 18 16 14 12 10 8 6 4 2 * Wildtype Fgf2 KO Diameter (µm) 9 8 7 6 5 4 3 2 1 * Wildtype Fgf2 KO 0 0 Vessel Area / 10X field (µm2) 600 500 400 300 200 100 Wildtype Fgf2 KO 0 n=6 *p<0.05 vs. wildtype
Future Directions Analysis of capillary density and vascular remodeling at early time points post IR injury Analysis of inflammatory response post IR injury
Acknowledgements Dave Ornitz Carla Weinheimer Attila Kovacs Sarah Davis Funding Sources American Heart Association Emergency Medicine Foundation Missouri ACEP