The Effects of Angiotensin Receptor Neprilysin Inhibitor on Endoplasmic Reticulum Stress in Doxorubicin‐Mediated Cardiomyopathy‐Associated Heart Failure Model in Rats

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.