Oxidative stress markers and transporters expression in the heart of fructose-fed rats treated with the cardiotoxic antineoplasic doxorubicin

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

Mar del Plata

Congreso; LXI Reunión Anual de la Sociedad Argentina de Investigación Clínica (SAIC); 2016

Sociedad Argentina de Investigación Clínica (SAIC)

Doxorubicin (DOX)clinical use as chemotherapeutic agent is limited due to the development of aprogressive cardiomyopathy and heart failure. Our interest is to study whetherthe cardiotoxicity of DOX could be increased in conditions related tocardiovascular risk factors. In this sense, we reported that in a model ofmetabolic syndrome caused by fructose-feeding (FRU) in rats, a single dose ofDOX decreased the ejection and shortening fractions in the left ventricle,suggesting greater cardiotoxicity than in control (C) animals. Both FRU and DOXproduce oxidative stress. Moreover, DOX changes the expression of the plasmamembrane transporter P-GP which extrudes DOX from cells. Also, a possiblemechanism of its cardiotoxicity is the depletion of carnitine which is uptakenby transporters OCTNs. The aim of this study was to analyze the effects of DOXon oxidative stress markers and expression of P-GP and OCTNs in cardiac tissueof C and FRU rats.  Male Sprague-Dawley rats receiving either tap water or water with 10% fructoseduring 8 weeks were treated with DOX (6mg/kg, ip, sd) or vehicle (ISS) (n=4/group). Three days after injection, ratswere sacrificed and left ventricles were excised to measure oxidative stressmarkers and perform western blot for P-GP and OCTN1/2/3. Both FRU and DOX enhanced TBARS production with asignificant increase in the FRU+DOX group compared to C (1.71±0.27 vs 0.97±0.11nmol/mg prot; p<0.05). There were no changes in superoxide dismutase andcatalase activities. The expression of P-GP in FRU was 55% lower than in C(p<0.01). DOX showed a tendency to increase P-GP expression, although FRU+DOXvalues remained 35% lower than C (p<0.01). Similar results were obtainedwith OCTNs. It is suggested that a minor efflux of DOX due to reducedexpression of P-GP and a possible depletion of carnitine related to decrease inOCTNs expression could contribute to the greater cardiotoxicity of DOX in FRUrats.