Sacubitril/valsartan reduces endoplasmic reticulum stress in a rat model of doxorubicin-induced cardiotoxicity
- Authors
- Kim, Byung Sik; Park, In-Hwa; Lee, A-Hyeon; Kim, Hyun-Jin; Lim, Young-Hyo; Shin, Jeong-Hun
- Issue Date
- Apr-2022
- Publisher
- SPRINGER HEIDELBERG
- Keywords
- Doxorubicin; Cardiotoxicity; Sacubitril; valsartan; Endoplasmic reticulum stress
- Citation
- ARCHIVES OF TOXICOLOGY, v.96, no.4, pp.1065 - 1074
- Indexed
- SCIE
SCOPUS
- Journal Title
- ARCHIVES OF TOXICOLOGY
- Volume
- 96
- Number
- 4
- Start Page
- 1065
- End Page
- 1074
- URI
- https://scholarworks.bwise.kr/hanyang/handle/2021.sw.hanyang/139011
- DOI
- 10.1007/s00204-022-03241-1
- ISSN
- 0340-5761
- Abstract
- The induction of endoplasmic reticulum (ER) stress has been reported as a key contributor to the cardiotoxicity of doxorubicin. Previous in vitro and in vivo studies suggest that sacubitril/valsartan, a novel angiotensin receptor-neprilysin inhibitor, could be effective against doxorubicin-induced cardiotoxicity. However, the precise mechanisms are not fully understood. Therefore, we investigated whether the cardioprotective effects of sacubitril/valsartan are associated with ER stress modulation in a rat model of doxorubicin-induced cardiotoxicity. Male Sprague-Dawley rats were treated with intraperitoneal injections of doxorubicin (15 mg/kg; cumulative) or saline for 3 weeks. From the day before the first treatment, control animals were gavaged daily with water (n = 8), whereas doxorubicin-treated animals were gavaged daily with water (n = 8) or sacubitril/valsartan (60 mg/kg/day; n = 8) for 6 weeks. Echocardiography was performed 6 weeks after the initiation of doxorubicin. In addition, serum troponin I and N-terminal brain natriuretic peptide levels were determined, and the extent of apoptosis and protein levels related to ER stress in the cardiac tissue and doxorubicin-treated H9c2 cardiomyocytes were analyzed. Sacubitril/valsartan significantly reduced doxorubicin-induced cardiac dysfunction and apoptosis in the myocardium. In addition, sacubitril/valsartan significantly downregulated the expression levels of proteins related to apoptosis and ER stress, including BAX, caspase 3, GRP78, PERK, IRE-1 alpha, ATF-6, eIF-2 alpha, ATF-4, and CHOP, in the myocardium of a rat model of doxorubicin-induced cardiotoxicity in vivo and doxorubicin-treated H9c2 cardiomyocytes in vitro. Sacubitril/valsartan significantly alleviated doxorubicin-induced cardiotoxicity, which may be associated with the reduction of ER stress.
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