This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 108/25/3140    most recent 01.CIR.0000105723.91637.1Cv1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by House, S. L. Articles by Schultz, J. E. J. Search for Related Content PubMed PubMed Citation Articles by House, S. L. Articles by Schultz, J. E. J. Related Collections Animal models of human disease Genetically altered mice Growth factors/cytokines Ischemic biology - basic studies

(Circulation. 2003;108:3140-3148.)
© 2003 American Heart Association, Inc.

Basic Science Reports

Cardiac-Specific Overexpression of Fibroblast Growth Factor-2 Protects Against Myocardial Dysfunction and Infarction in a Murine Model of Low-Flow Ischemia

Stacey L. House, BS; Craig Bolte, BA; Ming Zhou, MD, PhD; Thomas Doetschman, PhD; Raisa Klevitsky, MD; Gilbert Newman, BS; Jo El J. Schultz, PhD

From the Departments of Pharmacology and Cell Biophysics, Molecular Genetics, Biochemistry, and Microbiology (M.Z., T.D.), University of Cincinnati, Ohio.

Correspondence to Jo El J. Schultz, PhD, Department of Pharmacology and Cell Biophysics, University of Cincinnati, 231 Albert Sabin Way, ML 0575, Cincinnati, OH 45267. E-mail schuljo{at}email.uc.edu

Received June 18, 2003; revision received August 15, 2003; accepted August 19, 2003.

Background— Preconditioning the heart before an ischemic insult has been shown to protect against contractile dysfunction, arrhythmias, and infarction. Pharmacological studies have suggested that fibroblast growth factor-2 (FGF2) is involved in cardioprotection. However, because of the number of FGFs expressed in the heart and the promiscuity of FGF ligand-receptor interactions, the specific role of FGF2 during ischemia-reperfusion injury remains unclear.

Methods and Results— FGF2-deficient (Fgf2 knockout) mice and mice with a cardiac-specific overexpression of all 4 isoforms of human FGF2 (FGF2 transgenic [Tg]) were compared with wild-type mice to test whether endogenous FGF2 elicits cardioprotection. An ex vivo work-performing heart model of ischemia was developed in which murine hearts were subjected to 60 minutes of low-flow ischemia and 120 minutes of reperfusion. Preischemic contractile function was similar among the 3 groups. After ischemia-reperfusion, contractile function of Fgf2 knockout hearts recovered to 27% of its baseline value compared with a 63% recovery in wild-type hearts (P<0.05). In FGF2 Tg hearts, an 88% recovery of postischemic function occurred (P<0.05). Myocardial infarct size was also reduced in FGF2 Tg hearts compared with wild-type hearts (13% versus 30%, P<0.05). There was a 2-fold increase in FGF2 release from Tg hearts compared with wild-type hearts (P<0.05). No significant alterations in coronary flow or capillary density were detected in any of the groups, implying that the protective effect of FGF2 is not mediated by coronary perfusion changes.

Conclusions— These results provide evidence that endogenous FGF2 plays a significant role in the cardioprotective effect against ischemia-reperfusion injury.

Key Words: ischemia • myocardial infarction • myocardial stunning • growth substances

This article has been cited by other articles:

				D. J. Hausenloy and D. M. Yellon Cardioprotective growth factors Cardiovasc Res, July 15, 2009; 83(2): 179 - 194. [Abstract] [Full Text] [PDF]

				K. J. Lavine and D. M. Ornitz Shared Circuitry: Developmental Signaling Cascades Regulate Both Embryonic and Adult Coronary Vasculature Circ. Res., January 30, 2009; 104(2): 159 - 169. [Abstract] [Full Text] [PDF]

				S. M. Black, J. M. DeVol, and S. Wedgwood Regulation of fibroblast growth factor-2 expression in pulmonary arterial smooth muscle cells involves increased reactive oxygen species generation Am J Physiol Cell Physiol, January 1, 2008; 294(1): C345 - C354. [Abstract] [Full Text] [PDF]

				J. A.I. Virag, M. L. Rolle, J. Reece, S. Hardouin, E. O. Feigl, and C. E. Murry Fibroblast Growth Factor-2 Regulates Myocardial Infarct Repair: Effects on Cell Proliferation, Scar Contraction, and Ventricular Function Am. J. Pathol., November 1, 2007; 171(5): 1431 - 1440. [Abstract] [Full Text] [PDF]

				S. L. House, S. J. Melhorn, G. Newman, T. Doetschman, and J. E. J. Schultz The protein kinase C pathway mediates cardioprotection induced by cardiac-specific overexpression of fibroblast growth factor-2 Am J Physiol Heart Circ Physiol, July 1, 2007; 293(1): H354 - H365. [Abstract] [Full Text] [PDF]

				K. J. Lavine, A. C. White, C. Park, C. S. Smith, K. Choi, F. Long, C.-c. Hui, and D. M. Ornitz Fibroblast growth factor signals regulate a wave of Hedgehog activation that is essential for coronary vascular development. Genes & Dev., June 15, 2006; 20(12): 1651 - 1666. [Abstract] [Full Text] [PDF]

				S. L. House, K. Branch, G. Newman, T. Doetschman, and J. E. J. Schultz Cardioprotection induced by cardiac-specific overexpression of fibroblast growth factor-2 is mediated by the MAPK cascade Am J Physiol Heart Circ Physiol, November 1, 2005; 289(5): H2167 - H2175. [Abstract] [Full Text] [PDF]

				G. Suzuki, T.-C. Lee, J. A. Fallavollita, and J. M. Canty Jr Adenoviral Gene Transfer of FGF-5 to Hibernating Myocardium Improves Function and Stimulates Myocytes to Hypertrophy and Reenter the Cell Cycle Circ. Res., April 15, 2005; 96(7): 767 - 775. [Abstract] [Full Text] [PDF]

				G.M Rubanyi The design and preclinical testing of Ad5FGF-4 to treat chronic myocardial ischaemia Eur. Heart J. Suppl., September 1, 2004; 6(suppl_E): E12 - E17. [Abstract] [Full Text]

				S. K Jimenez, F. Sheikh, Y. Jin, K. A Detillieux, J. Dhaliwal, E. Kardami, and P. A Cattini Transcriptional regulation of FGF-2 gene expression in cardiac myocytes Cardiovasc Res, June 1, 2004; 62(3): 548 - 557. [Abstract] [Full Text] [PDF]