Apelin-13 attenuates cisplatin-induced cardiotoxicity through inhibition of ROS-mediated DNA damage and regulation of MAPKs and AKT pathways

Abstract

Platinum-based chemotherapy represents one of the most effective ways in combating human cancers. However, the cardiotoxicity subsequent severely limited its clinical application. Increased evidences indicate that oxidative stress plays a crucial role in the pathological process of platinum-induced cardiotoxicity. It is reported that apelin-13 a bioactive peptide has the scavenging capacity of free radical, and it has the potential to regulate the cardiovascular system. Hence, the potential of apelin-13 to antagonize cisplatin-induced cardiotoxicity was evaluated in H9c2 rat myocardial cells in vitro and in C57 mice in vivo. The results showed that cisplatin indeed caused DNA damage in H9c2 cells by promoting the accumulation of intracellular reactive oxygen species (ROS) and superoxide anion, which led to cell apoptosis and resulted in overt cardiotoxicity. However, apelin-13 pre-treatment effectively attenuated the cisplatin-induced ROS and superoxide anion generation, inhibited DNA damage, and suppressed the PARP cleavage and caspases activation. Further investigation revealed that apelin-13 blocked cisplatin-induced H9c2 cells apoptosis involving the regulation of MAPKs and PI3K/Akt signaling pathway. Importantly, apelin-13 co-treatment also significantly attenuated cisplatin-induced cardiotoxicity in vivo by inhibiting myocardial cells apoptosis and improving angiogenesis in mice heart. Taken together, our results suggest that the use of apelin-13 may be an effective strategy for antagonizing the cardiotoxicity-induced by platinum-based chemotherapy.

Protective effects of trimetazidine and coenzyme Q10 on cisplatin-induced cardiotoxicity by alleviating oxidative stress and mitochondrial dysfunction

“…Evidence has shown that cisplatin chemotherapy can lead to cardiotoxicity (8,26). This is in agreement with the present study where cisplatin significantly inhibited cell viability and induced apoptosis of rat cardiomyocytes.…”

“…In the present study, loss of ΔΨm and release of cyto-c into cytosol were observed in rat cardiomyocytes treated with cisplatin. Cyto-c translocation into the cytosol often precedes ΔΨm loss and is regarded as a sign of severe mitochondrial damage (34), which can subsequently induce caspase-dependent apoptosis of cardiomyocytes (8,26). However, these disruptions caused by cisplatin can be improved by TMZ and CoQ10, suggesting that TMZ and CoQ10 may inhibit cell apoptosis partially through suppressing cisplatin-induced mitochondrial dysfunction.…”

Cisplatin-activated PAI-1 secretion in the cancer-associated fibroblasts with paracrine effects promoting esophageal squamous cell carcinoma progression and causing chemoresistance

“…A variety of chemotherapy drugs can disturb the mitochondrial respiratory chain and generate ROS that increase oxidative stress and cell death. 23 ROS generation plays a critical role in the therapeutic effects of cisplatin. To examine the effect of PAI-1 on the ROS induced by cisplatin in the tumor cells, we detected the total ROS levels in ESCC cells using DCFH-DA.…”

Apelin protects against sepsis‑induced cardiomyopathy by inhibiting the TLR4 and NLRP3 signaling pathways

“…Apelin is a peptide hormone, which is widely expressed in various tissues, and was recently identified as an endogenous ligand for a G-protein-coupled receptor (19,20). Apelin has an important role in regulating phosphoinositide 3-kinase/Akt signaling-mediated angiectasis, inflammatory responses and cell proliferation (21). A recent study has also reported that anti-inflammatory effects were regulated by apelin/NF-κB signaling (22).…”