The Effects of Angiotensin Receptor Neprilysin Inhibitor on Endoplasmic Reticulum Stress in Doxorubicin-Mediated...

One of the most serious complications associated with the use of the chemotherapeutic agent doxorubicin (DOX) is cardiomyopathy. Although cardioprotective drugs such as angiotensin receptor-neprilysin inhibitors (ARNI) are used to prevent cardiomyopathy in DOX patients, no studies have reported the relationship between ARNI and endoplasmic reticulum (ER) stress in DOX-mediated cardiomyopathy. The aim of the present study was to investigate the possible changes in the GRP78 protein associated with ER stress in the heart failure model developed by DOX-induced cardiomyopathy in rats and to evaluate whether ARNI (LCZ696) given for treatment is effective on this protein. Male Wistar albino rats were divided into five groups: control, DOX, ARNI, DOX + ARNI, and post-DOX/ARNI. Body weights were monitored. Heart tissue sections were stained with hematoxylin-eosin. GRP78 expression was assessed with immunohistochemical labelling. The body weights of the rats in the DOX and post-DOX/ARNI groups were significantly reduced compared with the control and ARNI groups. Less degenerative changes were revealed in cardiomyocytes in the DOX + ARNI group compared with the cardiomyocytes in both the DOX and post-DOX/ARNI groups. When comparing the intensity of GRP78 staining, the intensity was significantly lower in the control, ARNI, and DOX + ARNI groups than in the DOX and post-DOX/ARNI groups. These results suggest that ARNI co-treatment mitigates ER stress and myocardial injury in DOX-induced cardiomyopathy. Therefore, ARNI may provide dual benefits in terms of both symptom management and cardioprotection during anthracycline chemotherapy.