Impact of corvitin and alpha-ketoglutarate on heart morphology, expression and activity of matrix metalloproteinases 2/9 in the heart of rats with doxorubicin-induced cardiomyopathy

The anthracycline anticancer drug doxorubicin is an effective and frequently used chemotherapeutic agent for various malignanciesbut it causes acute ventricular dysfunction, and also induces cardiomyopathy and heart failure. One of the mechanisms ofcardiotoxicity of doxorubicin is oxidative stress, which stimulates myocardial remodeling. Matrix metalloproteinases MMP2 andMMP9 play a key role in this process. Despite extensive research, the expression and activity of these enzymes in the doxorubicindamagedheart and the effect of antioxidants on these indicators have not been sufficiently studied. The aim of this work was tostudy the possible cardioprotective effect of the antioxidant drugs corvitin and alpha-ketoglutarate in rats with doxorubicininducedcardiomyopathy. Cardiomyopathy in rats was induced by intraperitoneal administration of doxorubicin at the dose of2.5 mg/kg body weight weekly for 28 days. Animals were divided into four groups: group 1 (control) received saline injections(2.5 mL/kg); group 2 – injections of doxorubicin, 3 – corvitin (5 mg/kg) 60 minutes before doxorubicin administration, 4 – doxorubicinand 1% solution of alpha-ketoglutarate in drinking water ad libitum. Heart weight and shape indexes, the ratio of muscleto connective tissues, and heart histology were examined 7 days after the end of drug administration. Activity of MMP2 andMMP9, their intracellular distribution in myocardial tissues were evaluated by gelatin-zymography and immunohistochemistry. Itwas found that doxorubicin cardiomyopathy in rats was accompanied by a decrease in heart weight index, adaptive change of heartshape from ellipsoid to globular, increase of connective tissue content. Administration of doxorubicin results in profound lesion of thecardiomyocytes of the atria and ventricle, manifested by excessive cytoplasmic expression of MMP2 and MMP9 and an increase theiractivity in the heart. Antioxidants corvitin and alpha-ketoglutarate have insufficient regenerative effect on mass and shape indexes ofheart however, exhibit potent cardioprotective effect by regulation of expression and activity of MMP2 and MMP9