title: FGF-2 and FGF-16 protect isolated perfused mouse hearts from acute doxorubicin-induced contractile dysfunction.
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.
authors: Department of Physiology, University of Manitoba, 745 Bannatyne Avenue, Winnipeg, MB, R3E 3J7, Canada.
authors: David P
authors: DP
authors: Sontag
authors: Jie
authors: J
authors: Wang
authors: Elissavet
authors: E
authors: Kardami
authors: Peter A
authors: PA
authors: Cattini
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents; D000903:Antibiotics, Antineoplastic / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D001794:Blood Pressure / Q000187:drug effects; D002316:Cardiotonic Agents; D003326:Coronary Circulation / Q000187:drug effects; D004317:Doxorubicin / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D004789:Enzyme Activation / Q000187:drug effects; D016222:Fibroblast Growth Factor 2 / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology*; D005346:Fibroblast Growth Factors / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology*; D006331:Heart Diseases / Q000139:chemically induced* / Q000517:prevention & control*; D066298:In Vitro Techniques; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D051379:Mice; D009200:Myocardial Contraction / Q000187:drug effects*; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology; D011493:Protein Kinase C / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D015427:Reperfusion Injury / Q000517:prevention & control; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D000889:Anti-Arrhythmia Agents; D000903:Antibiotics, Antineoplastic; D002316:Cardiotonic Agents; C484686:Fgf16 protein, mouse; D011994:Recombinant Proteins; D016222:Fibroblast Growth Factor 2; D005346:Fibroblast Growth Factors; D004317:Doxorubicin; D007770:L-Lactate Dehydrogenase; D011493:Protein Kinase C