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FGF-2 and FGF-16 Protect Isolated Perfused Mouse Hearts from Acute Doxorubicin-Induced Contractile Dysfunction

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Abstract

The anti-cancer drug doxorubicin is associated with an increased risk of cardiac damage and dysfunction, which can be acute as well as chronic. Fibroblast growth factor 2 (FGF-2) provides cardioprotection from ischemia–reperfusion injury but its effects on doxorubicin-induced damage are not known. We investigated the acute effects of doxorubicin administered in the absence and presence of FGF-2 pre-treatment, on isolated mouse perfused heart function over a period of 120 min. Doxorubicin elicited a significant decrease in left ventricular developed pressure (DP) at 30 min that persisted throughout the study. No effect on lactate dehydrogenase levels was detected in the perfusate, suggesting a lack of significant plasma membrane damage. FGF-2 pre-treatment lessened the deleterious effect of doxorubicin on DP significantly, and this beneficial effect of FGF-2 was blunted by protein kinase C inhibition with chelerythrine. Pre-treatment with a non-mitogenic FGF-2 mutant or FGF-16 also protected against a doxorubicin-induced decrease in DP. FGF-16 as well as FGF-2 pre-treatment elicited a small and transient negative inotropic effect. In conclusion, FGF-2 and FGF-16 increase resistance to acute doxorubicin-induced cardiac dysfunction, and protein kinase C activation is implicated in this response.

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Acknowledgments

These studies were supported by a Grant from the Heart and Stroke Foundation of Canada (PAC) and the Canadian Institutes of Health Research (EK; FRN-74733).

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Authors and Affiliations

  1. Department of Physiology, University of Manitoba, 745 Bannatyne Avenue, Winnipeg, MB, R3E 3J7, Canada

    David P. Sontag, Jie Wang & Peter A. Cattini

  2. Department of Human Anatomy and Cell Science, University of Manitoba, 745 Bannatyne Avenue, Winnipeg, MB, R3E 3J7, Canada

    Elissavet Kardami

  3. Institute of Cardiovascular Science, St. Boniface Hospital Research Centre, Winnipeg, MB, R2H 2A6, Canada

    Elissavet Kardami

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  1. David P. Sontag
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  2. Jie Wang
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  4. Peter A. Cattini
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Correspondence to Peter A. Cattini.

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David P. Sontag and Jie Wang contributed equally to this work.

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Sontag, D.P., Wang, J., Kardami, E. et al. FGF-2 and FGF-16 Protect Isolated Perfused Mouse Hearts from Acute Doxorubicin-Induced Contractile Dysfunction. Cardiovasc Toxicol 13, 244–253 (2013). https://doi.org/10.1007/s12012-013-9203-5

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