Exendin-4 improves mitochondrial integrity against cisplatin-induced cardiac damage: Targeting p53 and NF-κB pathways

Heart failure is a devastating consequence of chemotherapy, with mitochondrial dysfunction playing a key role in cardiac damage. Cisplatin (CP), a widely used chemotherapeutic agent, induces cardiotoxicity by increasing Apoptosis and triggering inflammation. This study provides evidence that exendin-4 (Ex-4), a glucagon-like peptide-1 (GLP-1) receptor agonist, exerts cardioprotective effects in H9c2 cardiomyoblasts against CP-induced injury. Ex-4 administration markedly restored mitochondrial bioenergetics, as evidenced by improved oxygen consumption and extracellular acidification rates, while preserving mitochondrial morphology and reversing fragmentation caused by CP. The observed effects were correlated with upregulation of markers involved in mitochondrial biogenesis (PGC1α, NRF1, ATP5A) and fusion process (OPA1, MFN1), accompanied by downregulation of mitochondrial fission markers (DNM1, FIS1). Ex-4 attenuated intracellular and mitochondrial Reactive Oxygen Species (ROS) levels, repressed Caspase-3/7 activity, and shifted apoptotic balance by enhancing Bcl-2 levels while diminishing Bax expression. Moreover, Ex-4 suppressed CP-triggered inflammatory responses by reducing TNFα and IL6 levels. Mechanistically, Ex-4 activated pro-survival signals (p-Akt and p-Erk1/2) and exerted cardioprotective effects through inhibition of p53 and NF-κB-dependent cascades. Pharmacological inhibition of p53 (pifithrin-α) or NF-κB (JSH-23) further amplified the protective effect of Ex-4 against CP-induced mitochondrial abnormalities, Apoptosis, and inflammation, whereas activation of p53 (nutlin-3) or NF-κB (NF-κB Activator 1) reversed these protective outcomes. Thus, Ex-4 emerges as a potent modulator of mitochondrial dysfunction and cellular stress through suppression of the p53 and NF-κB pathways, offering a promising therapeutic approach to mitigate CP-induced cardiotoxicity.

Cardiotoxicity; Cisplatin; Exendin-4; Mitochondrial dysfunction; NF-κB; p53.