Profile of Molecular Markers of Cardiac Fibrosis in Rats Exposed to Different Doxorubicin Doses

The study is devoted to investigating the profile of molecular markers of fibrosis in Wistar rats exposed to different doses of doxorubicin. Forty male Wistar rats weighing 260 ± 19 g were divided into 4 groups: one control and three experimental groups corresponding to different cumulative doses of doxorubicin (5, 10, 15 mg/kg, i.p.), each administered 6 times every third day. After reaching cumulative doses, animals were under observation for 2 months. At the end of the observation period, rat hearts were taken for molecular and morphological studies. Histological, echocardiographic and molecular analyses revealed doxorubicin-induced dose-dependent lesions in the left ventricular myocardium. In all three experimental groups, TGF-β expression level was indistinguishable from the control. At the same time, animals treated with a maximum cumulative dose of doxorubicin (15 mg/kg) retained increased expression of type I and II collagen, ET-1, FGF4 and TNF-α, which suggested, on the one hand, an incomplete formation of fibrous connective tissue and, on the other hand, an active involvement of these markers of cardiac fibrosis in inflammatory processes against the background of pronounced cardiotoxic effect of the chemotherapy drug. In animals administered with a medium doxorubicin dose (10 mg/kg), expression levels of the above molecular markers did not differ from those in the control group, whereas the treatment with a minimum dose (5 mg/kg) led to a decrease in the expression of type I and II collagen, ET-1 and TNF-α, but an increase in FGF4 expression levels.