Abstract
In addition to the known antitumour effects of ursolic acid (UA), increasing evidence indicates that this molecule plays a role in cardiac protection. In this study, the effects of ursolic acid on the heart in mice treated with doxorubicin (DOX) were assessed. The results showed that ursolic acid improved left ventrical fractional shortening (LVFS) and left ventrical ejection fraction (LVEF) of the heart, increased nitrogen oxide (NO) levels, inhibited reactive oxygen species (ROS) production and decreased cardiac apoptosis in mice treated with doxorubicin. Mechanistically, ursolic acid increased AKT and endothelial nitric‐oxide synthase (eNOS) phosphorylation levels, and enhanced eNOS expression, while inhibiting doxorubicin induced eNOS uncoupling through NADPH oxidase 4 (NOX4) down‐regulation. These effects of ursolic acid resulted in heart protection from doxorubicin‐induced injury. Therefore, ursolic acid may be considered a potential therapeutic agent for doxorubicin‐associated cardiac toxicity in clinical practice.
Highlights
The results showed that ursolic acid prevents cardiac toxicity after doxorubicin treatment by increasing the phosphorylation levels of AKT and endothelial nitric‐oxide synthase (eNOS), and inhibiting eNOS uncoupling through NADPH oxidase 4 (NOX4) down‐regulation
To assess the effects of ursolic acid on cardiac cell apoptosis in mice treated with doxorubicin in the early injury phase, mice in each group were killed 1 week after ursolic acid treatment, and heart specimens were harvested for Terminal dUTP nick end‐labelling (TUNEL) staining
The results showed that ursolic acid significantly increased the phosphorylation levels of AKT and eNOS in the mouse heart after doxorubicin treatment (Figure 5A‐D), which indicated that the AKT‐eNOS pathway played an important role in the anti‐apoptotic effects of ursolic acid in cardiac cells
Summary
Doxorubicin was purchased from Aladdin Industrial Company (Shanghai, China, purity 98%). Killed at 1 week after doxorubicin treatment was serially sectioned at 4 μm thickness and incubated with 2,7‐dichlorofluorescin diacetate (DCFH‐DA) (20 μmol L−1) (ROS assay kit, Nanjing Jiancheng Bioengineering Corporation, China, E004) at 37°C for 60 minutes in the dark. The CKMB measurement was done as previously reported.[6] In brief, five mice in each group were killed on day 7 after doxorubicin treatment, and the blood samples were withdrawn immediately through the right atrium. Snap frozen heart samples obtained at 7 days after treatment with doxorubicin were washed twice with cold PBS and resuspended in cold lysis buffer containing 20 mmol/L HEPES (pH 7.5), 150 mmol/L NaCl, 1 mmol/L EDTA, 0.5% Triton X‐100 and protease inhibitors (Roche). Five mice in each group were killed at 28 days after doxorubicin treatment, and heart samples were harvested, paraffin embedded and cut into 4 μm thick sections.
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