Cariporide Attenuates Doxorubicin-Induced Cardiotoxicity in Rats by Inhibiting Oxidative Stress, Inflammation and Apoptosis Partly Through Regulation of Akt/GSK-3β and Sirt1 Signaling Pathway

Abstract

Background: Doxorubicin (DOX) is a potent chemotherapeutic agent with limited usage due to its cumulative cardiotoxicity. The Na+/H+ exchanger isoform 1 (NHE1) is a known regulator of oxidative stress, inflammation, and apoptosis. The present study was designed to investigate the possible protective effect of cariporide (CAR), a selective inhibitor of NHE1, against DOX-induced cardiotoxicity in rats.Methods: Male Sprague-Dawley rats were intraperitoneally injected with DOX to induce cardiac toxicity and CAR was given orally for treatment. The injured H9c2 cell model was established by incubation with DOX in vitro. Echocardiography, as well as morphological and ultra-structural examination were performed to evaluate cardiac function and histopathological changes. The biochemical parameters were determined according to the manufacturer’s guideline of kits. ROS were assessed by using an immunofluorescence assay. The serum levels and mRNA expressions of inflammatory cytokines were measured by using ELISA or qRT-PCR. Cardiac cell apoptosis and H9c2 cell viability were tested by TUNEL or MTT method respectively. The protein expressions of Cleaved-Caspase-3, Bcl-2, Bax, Akt, GSK-3β, and Sirt1 were detected by western blot.Results: Treatment with CAR protected against DOX-induced body weight changes, impairment of heart function, leakage of cardiac enzymes, and heart histopathological damage. In addition, CAR significantly attenuated oxidative stress and inhibited the levels and mRNA expressions of inflammatory cytokines (TNF-α, IL-6, IL-18, and IL-1β), which were increased by DOX treatment. Moreover, CAR significantly suppressed myocardial apoptosis and Cleaved-Caspase-3 protein expression induced by DOX, which was in agreement with the increased Bcl-2/Bax ratio. Also, DOX suppressed phosphorylation of Akt and GSK-3β, which was significantly reversed by administration of CAR. Furthermore, CAR treatment prevented DOX-induced down-regulation of Sirt1 at the protein level in vitro and in vivo. Finally, Sirt1 inhibitor reversed the protective effects of CAR, as evidenced by reduced cell viability and Sirt1 protein expression in vitro.Conclusion: Taken together, we provide evidence for the first time in the current study that CAR exerts potent protective effects against DOX-induced cardiotoxicity in rats. This cardio-protective effect is attributed to suppressing oxidative stress, inflammation, and apoptosis, at least in part, through regulation of Akt/GSK-3β and Sirt1 signaling pathway, which has not been reported to date.

Carnosic acid protects against doxorubicin-induced cardiotoxicity through enhancing the Nrf2/HO-1 pathway

“…Translocation of Bax from the cytoplasm to the mitochondria promotes the release of cytochrome c from the mitochondria to activate caspase3, whereas Bcl-2 prevents the release of cytochrome c from the mitochondria and thus inhibits the process of apoptosis. 30 In our study, we also found that CA treatment significantly ameliorated DOX-induced apoptosis in cardiomyocytes and cardiac tissues, as indicated by the decreased activation of Bax, along with restored Bcl-2 expression levels. Indeed, activating Nrf2 via CA could decrease DOX-induced cardiomyocyte apoptosis and the inhibition of Nrf2 abolished this protective effect provided by CA.…”

Ticagrelor reduces doxorubicin-induced pyroptosis of rat cardiomyocytes by targeting GSK-3β/caspase-1

“…Pyroptosis mainly occurs via the canonical caspase-1-dependent pathway, and we examined whether Dox caused pyroptosis in rat cardiomyocytes through the activation of caspase-1. GSK-3β, has been proved to play a role in Dox induced cardiotoxicity (20,21). Our results showed that after Dox administration, the proportion of p-GSK-3β positive heart slices decreased (Figures 2A, B) and cleaved-caspase-1 increased (Figures 2A, C).…”

“…Our recent study revealed that GSK-3β regulate pyroptosis (19). GSK-3β contributes to Dox-induced cardiotoxicity by mediating oxidative stress, inflammation and apoptosis (20). Therefore, we want to determine whether GSK-3β mediated pyroptosis is the key to DOX induced cardiotoxicity.…”

Berberine efficacy against Doxorubicin-induced cardiotoxicity: A systematic review

“…Other review studies also show that the mechanism of cardiotoxicity caused by other drugs is still unclear. However, various reasons such as oxidative stress, apoptosis, and inflammation can aggravate this condition (31)(32)(33)(34).…”