The Protective Effects of Gap26, a New Connexin-43 Inhibitor, on Doxorubicin-Induced Cardiotoxicity in Rats

Doxorubicin (Dox) is a potent chemotherapeutic agent. Its clinical use is limited by severe cardiotoxicity, driven largely by oxidative stress. Gap junctions, formed by connexin-43 (Cx43), are vital for cardiac function, and pathological stress can open Cx43 hemichannels, exacerbating cellular damage. We hypothesized that Gap26, a Cx43 inhibitor, could protect against Dox-induced cardiotoxicity. Male Wistar rats were randomly assigned to four groups: Control/Saline, Control/Gap26, Dox/Saline, and Dox/Gap26 (receiving Gap26 pretreatment). After 14 days, cardiac function was assessed by electrocardiography (ECG) and inotropic studies. Myocardial histopathology and levels of malondialdehyde (MDA) and glutathione (GSH) were also evaluated. Dox significantly impaired cardiac contractility, markedly reducing atrial contractile force compared to the Control/Saline group. Histopathological analysis showed that Dox treatment led to severe myopathy and fibrosis. Dox also significantly increased MDA and depleted GSH. In contrast, Gap26 pretreatment significantly restored atrial contractility, attenuated histopathological damage, and ameliorated both MDA and GSH levels. Gap26 also demonstrated a shift towards less severe arrhythmias in subjects receiving Dox. Gap26 exhibited significant protection against Dox-induced cardiotoxicity by preserving atrial function, reducing oxidative damage, and improving myocardial histopathology. These findings suggest Gap26 may be a promising therapeutic candidate for preventing Dox cardiotoxicity.