title: Overweight in mice, induced by perinatal programming, exacerbates doxorubicin and trastuzumab cardiotoxicity.
abstract: OBJECTIVE
  Trastuzumab (TRZ) is believed to potentiate doxorubicin (DOX) cardiotoxicity, resulting in left ventricular dysfunction. There is some evidence that overweight could influence anticancer drug-induced cardiotoxicity, though no study has evaluated the impact of moderate overweight, induced by postnatal nutritional programming, on the cardiotoxic effects of DOX alone or in combination with TRZ.
  
  
  METHODS
  Immediately after birth, litters of C57BL/6 mice were either maintained at 9 pups (normal litter, NL) or reduced to 3 (small litter, SL) in order to induce programming of ~15 % overweight through postnatal overfeeding. At 4 months, NL and SL mice received a single intra-peritoneal injection of either saline, DOX (6 mg/kg), TRZ (10 mg/kg) or both (DOX-TRZ). Transthoracic echocardiography was performed 24 h before as well as 10 and 20 days after treatments.
  
  
  RESULTS
  Twenty days after DOX administration, systolic dysfunction was observed only in the overweight SL group, while NL mice group had a normal left ventricular ejection fraction. However, in the NL group, functional impairment appeared when TRZ was co-administered. Forty-eight hours after drug administration, gene expression of natriuretic peptides (ANP, BNP) appeared to be potentiated in DOX-TRZ mice of both the NL and SL group, whereas the expression of β-MHC increased significantly in overweight SL mice only.
  
  
  CONCLUSIONS
  In an acute model of DOX cardiotoxicity, moderately overweight adult mice were more sensitive to cardiac systolic impairment. Moreover, our results confirm the potentiating action of TRZ on DOX-induced cardiotoxicity in lean mice.
authors.affiliation: Laboratoire de Physiopathologie et Pharmacologie Cardio-Métaboliques (LPPCM), Inserm UMR866, Faculties of Health Sciences, University of Bourgogne-Franche-Comte, 7 Bd Jeanne d'Arc, 21000, Dijon, France.|Cardiology Department, University Hospital, Dijon, France.
authors.forename: Charles
authors.initials: C
authors.lastname: Guenancia
authors.affiliation: Laboratoire de Physiopathologie et Pharmacologie Cardio-Métaboliques (LPPCM), Inserm UMR866, Faculties of Health Sciences, University of Bourgogne-Franche-Comte, 7 Bd Jeanne d'Arc, 21000, Dijon, France.|Cardiology Department, University Hospital, Dijon, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Hachet
authors.affiliation: Laboratoire de Physiopathologie et Pharmacologie Cardio-Métaboliques (LPPCM), Inserm UMR866, Faculties of Health Sciences, University of Bourgogne-Franche-Comte, 7 Bd Jeanne d'Arc, 21000, Dijon, France.|Pharmacology Group, Medicinal and Pharmaceutical Chemistry Department, Pharmaceutical and Drug Industries Research Division, National Research Centre (ID: 60014618), 33 El Bohouth St., Dokki, P.O. 12622, Giza, Egypt.
authors.forename: Mona
authors.initials: M
authors.lastname: Aboutabl
authors.affiliation: Laboratoire de Physiopathologie et Pharmacologie Cardio-Métaboliques (LPPCM), Inserm UMR866, Faculties of Health Sciences, University of Bourgogne-Franche-Comte, 7 Bd Jeanne d'Arc, 21000, Dijon, France.
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.affiliation: Laboratoire de Physiopathologie et Pharmacologie Cardio-Métaboliques (LPPCM), Inserm UMR866, Faculties of Health Sciences, University of Bourgogne-Franche-Comte, 7 Bd Jeanne d'Arc, 21000, Dijon, France.
authors.forename: Eve
authors.initials: E
authors.lastname: Rigal
authors.affiliation: Laboratoire de Physiopathologie et Pharmacologie Cardio-Métaboliques (LPPCM), Inserm UMR866, Faculties of Health Sciences, University of Bourgogne-Franche-Comte, 7 Bd Jeanne d'Arc, 21000, Dijon, France.|Cardiology Department, University Hospital, Dijon, France.
authors.forename: Yves
authors.initials: Y
authors.lastname: Cottin
authors.affiliation: Laboratoire de Physiopathologie et Pharmacologie Cardio-Métaboliques (LPPCM), Inserm UMR866, Faculties of Health Sciences, University of Bourgogne-Franche-Comte, 7 Bd Jeanne d'Arc, 21000, Dijon, France.
authors.forename: Luc
authors.initials: L
authors.lastname: Rochette
authors.affiliation: Laboratoire de Physiopathologie et Pharmacologie Cardio-Métaboliques (LPPCM), Inserm UMR866, Faculties of Health Sciences, University of Bourgogne-Franche-Comte, 7 Bd Jeanne d'Arc, 21000, Dijon, France. cvergely@u-bourgogne.fr.
authors.forename: Catherine
authors.initials: C
authors.lastname: Vergely
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D066126:Cardiotoxicity; D004317:Doxorubicin / Q000633:toxicity*; D005260:Female; D006321:Heart / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D050177:Overweight / Q000150:complications*; D000068878:Trastuzumab / Q000633:toxicity*; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D004317:Doxorubicin; D000068878:Trastuzumab
keywords: Cardiotoxicity; Doxorubicin; Overweight; Postnatal programming; Trastuzumab