title: Protection by endogenous FGF-2 against isoproterenol-induced cardiac dysfunction is attenuated by cyclosporine A.
abstract: Fibroblast growth factor-2 (FGF-2) is implicated in cardioprotection. However, previously we found that chronic elevation in cardiac FGF-2 levels in transgenic mice was associated with exaggerated, cyclosporine A-preventable, cellular infiltration after isoproterenol-induced injury, suggestive of an adverse outcome, although this was not examined with functional studies. We have now used highly sensitive tissue Doppler imaging (TDI) to evaluate cardiac functional parameters after isoproterenol administration in transgenic mice overexpressing the 18 kDa FGF-2 in the heart in vivo. Cardiac function was assessed in conscious FGF-2 transgenic and non-transgenic mice at 24 h as well as 2 and 4 weeks after isoproterenol administration, and in the absence or presence of either cyclosporine A or anti-CD3ε treatments. Isoproterenol decreased left ventricular endocardial velocity and strain rate by 47-51% at 24 h in non-transgenic mice, but to a significantly lesser extent (by 24%) in transgenic mice. While additional decreases were seen in non-transgenic mice at 2 weeks, there was no further reduction in ventricular endocardial velocity or strain rate up to 4 weeks post-treatment in FGF-2 transgenic mice. Functional improvement at 2 and 4 weeks post-isoproterenol was reduced significantly by treatment with cyclosporine A but not anti-CD3ε; the latter targets T lymphocyte activation more specifically. TDI values in the presence of chronic FGF-2 overexpression are prognostic of an improved cardiac outcome and protection from isoproterenol induced cardiac dysfunction in vivo. Our data also suggest that cyclosporine A-sensitive infiltrating cell population(s) may contribute to the sustained beneficial effect of FGF-2 in vivo.
authors.affiliation: Department of Physiology, University of Manitoba, Winnipeg, MB R3E 3J7, Canada.
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Jimenez
authors.forename: Davinder S
authors.initials: DS
authors.lastname: Jassal
authors.forename: Elissavet
authors.initials: E
authors.lastname: Kardami
authors.forename: Peter A
authors.initials: PA
authors.lastname: Cattini
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D016572:Cyclosporine / Q000494:pharmacology*; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000378:metabolism*; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D018608:Ultrasonography, Doppler; D018754:Ventricular Dysfunction / Q000139:chemically induced* / Q000000981:diagnostic imaging / Q000378:metabolism*
chemical_list: D000318:Adrenergic beta-Agonists; D016222:Fibroblast Growth Factor 2; D016572:Cyclosporine; D007545:Isoproterenol