Background/Objectives: Anthracyclines remain a pivotal element of numerous tumor management regimens; however, their utilization is associated with a range of adverse effects, the most significant of which is cardiotoxicity. Research is constantly being conducted to identify substances that could be incorporated into ongoing cancer chemotherapy to mitigate anthracycline-induced cardiotoxicity. Recently, the apelinergic system has received a lot of attention in this field due to its involvement in cardiovascular regulation. Therefore, the aim of our study was to investigate the ability of the apelinergic system to inhibit the cardiotoxic effects of anthracycline—doxorubicin (DOX). Methods: In this study, 54 Sprague–Dawley rats were divided into seven groups and received intraperitoneal injections with DOX once a week for 4 consecutive weeks. The osmotic pumps provided a continuous release of NaCl (control groups), apelin-13 and elabela at two different doses, and the apelin receptor (APJ) antagonist ML221. Electrocardiography (ECG) and transthoracic echocardiography (TTE) with assessment of left ventricular (LV) systolic parameters were conducted on the first and last days of the experiment. Results: Lower doses of APJ agonists prevented the prolongation of QT and QTc intervals induced by DOX, while higher doses of these drugs exerted no such effect. The TTE examination confirmed DOX-induced LV systolic dysfunction. Moreover, the TTE examination revealed an improvement in the LV systolic parameters in the DOX-treated groups that were simultaneously administered APJ agonists. Conclusions: Our findings support the use of apelin and elabela as potential cardioprotective agents against anthracycline-induced cardiotoxicity.

Background: Doxorubicin, a widely used chemotherapeutic agent, has been shown to increase reactive oxygen species (ROS) levels, disrupting cellular homeostasis not only in cancer cells but also in healthy tissues, particularly in cardiomyocytes, which leads to chemotherapy-induced cardiotoxicity. Therefore, new strategies are continually being explored to mitigate these adverse effects. One such approach is the use of additional substances with cardioprotective properties during doxorubicin therapy. A promising candidate is elabela, a peptide of the apelinergic system, which may exert protective effects against doxorubicin-induced oxidative stress in cardiomyocytes. Objectives: This study aims to evaluate the modulatory effects of elabela on oxidative stress markers, malondialdehyde (MDA) and 8-hydroxy-2′-deoxyguanosine (8-OHdG) in the left ventricle of the myocardium following chronic doxorubicin administration in rats. Material and Methods: 32 male, 12-week-old Sprague-Dawley rats (SPRD) were randomly assigned to four experimental groups. For 28 days, all animals received continuous infusions (2.5 μL/h) via subcutaneously implanted osmotic pumps of 0.9% NaCl or elabela (40 μg/kg body weight/day or 200 μg/kg body weight/day). Simultaneously, animals were injected intraperitoneally 4 times at weekly intervals with 0.9% NaCl or DOX (3.5 mg/kg body weight). Next, the animals were sacrificed, and left ventricular (LV) cardiac tissue was collected for further analysis. MDA and 8-OHdG and elabela level in LV lysate were assessed by ELISA. The Ela expression in LV was quantified by Real-Time PCR. The TUNEL assay, labeled with a 5′-triphosphate strand, was used to assess the degree of apoptosis. Results: DOX treatment decreased both the Ela expression and elabela levels in the LV. Elabela administration at a dose of 200 µg/kg body weight/day significantly decreased ELA levels and Ela expression compared to the control group. The level of 8-OhdG was unexpectedly decreased in the DOX group compared to controls, while elabela treatment at both doses restored 8-OHdG levels observed in the control group. However, TUNEL staining demonstrated that elabela administration at 200 µg/kg body weight/day reduced the number of apoptotic cardiomyocytes compared to the DOX-only group, indicating a protective effect against DOX-induced apoptosis. The lower dose of 40 µg/kg body weight/day showed a moderate, non-significant attenuation of apoptosis. Conclusions: Elabela showed a protective effect against DOX-induced cardiomyocyte apoptosis in the LV by promoting processes that reduce oxidative stress in cardiac cells.

Doxorubicin-induced cardiotoxicity is closely associated with oxidative stress (OS), and apelin-13 has been proposed as a potential cardioprotective peptide. However, its effects on specific oxidative stress (OS) markers remain poorly understood. This preliminary study aimed to evaluate the impact of apelin-13 on oxidative stress markers in rats chronically treated with doxorubicin (DOX). Male rats received DOX with or without apelin-13 (40 µg/kg body weight/day). The levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG) and malondialdehyde (MDA) were measured as indicators of oxidative DNA damage and lipid peroxidation, respectively. The DOX treatment resulted in increased MDA levels, which were unaffected by apelin-13. Conversely, 8-OHdG levels decreased with DOX alone but returned to baseline levels in the presence of DOX and apelin-13. In conclusion, while apelin-13 did not mitigate DOX-induced lipid oxidative damage, it may selectively influence nuclear OS markers. This suggests a complex and context-dependent role of apelin-13 in modulating oxidative stress associated with DOX treatment.