Cardiotoxic effects of the antineoplasic doxorubicin in a model of metabolic syndrome: oxidative stress and transporters expression in the left ventricle

KOUYOUMDZIAN NM; OGONOWSKI N; RUKAVINA MIKUSIC NL; FELLET A; ROSON MI; CHOI MR; BALASZCZUK AM; CELUCH SM

Mar del Plata

Congreso; LXIII Reunión Anual de la Sociedad Argentina de Investigación Clínica (SAIC); 2018

Sociedad Argentina de Investigación Clínica (SAIC)

Doxorubicin (DOX) clinical use as chemotherapeutic agent is limiteddue to the development of cardiomyopathies and heart failure.In the present study we aimed to examine whether Metabolic Syndrome-like conditions in rats, generated by administration of 10%fructose in the drinking water, modify the adverse effects inducedby a single dose of DOX and whether the treatment modifies theexpression of P-glycoprotein (P-gp) and organic cation/carnitinetransporter OCT-N2 in the heart.Male Sprague-Dawley rats receiving either tap water (C, control) orwater with 10% fructose (F) during 8 weeks were treated with DOX(6 mg/kg, ip, md) or vehicle (V) (n=4/group). Three days after injection,echocardiographic monitoring was performed and then ratswere sacrificed. Left ventricles were excised to measure oxidativestress markers and protein expression of P-gp and OCTN1/2/3 bywestern blot.F increased TBARS tissue levels and decreased the activity of theantioxidant enzyme SOD (p<0.01). It is of note that DOX injectionproduced a further increase in TBARS tissue levels in F rats(p<0.001) whereas it had no effect in C animals. DOX decreasedejection fraction and fractional shortening in F rats (p<0.05) but hadno effects in C animals. P-gp protein levels were significantly lowerin F than in C animals (p<0.05). DOX did not modify P-gp expressionin C animals but caused a decrease in the F group (p<0.01). On theother hand, OCT-N1/2/3 protein levels did not change with either Foverload or the administration of DOX.Therefore, it is suggested that a minor efflux of DOX due to a reducedexpression of P-gp could contribute to the greater cardiotoxicityof DOX in F rats. Supported by CONICET (PIP 112-201201-00425).