title: Acute doxorubicin-induced cardiotoxicity is associated with matrix metalloproteinase-2 alterations in rats.
abstract: BACKGROUND
  Doxorubicin can cause cardiotoxicity. Matrix metalloproteinases (MMP) are responsible for degrading extracellular matrix components which play a role in ventricular dilation. Increased MMP activity occurs after chronic doxorubicin treatment. In this study we evaluated in vivo and in vitro cardiac function in rats with acute doxorubicin treatment, and examined myocardial MMP and inflammatory activation, and gene expression of proteins involved in myocyte calcium transients.
  
  
  METHODS
  Wistar rats were injected with doxorubicin (Doxo, 20 mg/kg) or saline (Control). Echocardiogram was performed 48 h after treatment. Myocardial function was assessed in vitro in Langendorff preparation.
  
  
  RESULTS
  In left ventricle, doxorubicin impaired fractional shortening (Control 0.59 ± 0.07; Doxo 0.51 ± 0.05; p < 0.001), and increased isovolumetric relaxation time (Control 20.3 ± 4.3; Doxo 24.7 ± 4.2 ms; p = 0.007) and myocardial passive stiffness. MMP-2 activity, evaluated by zymography, was increased in Doxo (Control 141338 ± 8924; Doxo 188874 ± 7652 arbitrary units; p < 0.001). There were no changes in TNF-α, INF-γ, IL-10, and ICAM-1 myocardial levels. Expression of phospholamban, Serca-2a, and ryanodine receptor did not differ between groups.
  
  
  CONCLUSIONS
  Acute doxorubicin administration induces in vivo left ventricular dysfunction and in vitro increased myocardial passive stiffness in rats. Cardiac dysfunction is related to myocardial MMP-2 activation. Increased inflammatory stimulation or changed expression of the proteins involved in intracellular calcium transients is not involved in acute cardiac dysfunction.
authors: Internal Medicine Department, Botucatu Medical School, Univ Estadual Paulista (UNESP), Brazil.
authors: Bertha Furlan
authors: BF
authors: Polegato
authors: Marcos Ferreira
authors: MF
authors: Minicucci
authors: Paula Schmidt
authors: PS
authors: Azevedo
authors: Robson Francisco
authors: RF
authors: Carvalho
authors: Fernanda
authors: F
authors: Chiuso-Minicucci
authors: Elenize Jamas
authors: EJ
authors: Pereira
authors: Sergio Alberto Rupp
authors: SA
authors: Paiva
authors: Leonardo Antônio Mamede
authors: LA
authors: Zornoff
authors: Marina Politi
authors: MP
authors: Okoshi
authors: Beatriz Bojikian
authors: BB
authors: Matsubara
authors: Luiz Shiguero
authors: LS
authors: Matsubara
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D066126:Cardiotoxicity / Q000209:etiology*; D004317:Doxorubicin / Q000633:toxicity*; D004452:Echocardiography; D006321:Heart / Q000187:drug effects / Q000502:physiology; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D007649:Ketamine / Q000494:pharmacology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014991:Xylazine / Q000494:pharmacology
chemical_list: D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D016753:Interleukin-10; D014991:Xylazine; D007649:Ketamine; D004317:Doxorubicin; D007371:Interferon-gamma; D020778:Matrix Metalloproteinase 2