Original ArticleFeedback Interaction Between Apelin and Endoplasmic Reticulum Stress in the Rat MyocardiumJin, Sheng PhD*; Wang, Yipu*; Ma, Liuchang*; Zhang, Jiaqi*; Huang, Panna*; Zhang, Haozhe*; Liu, Xinxia PhD†; Wu, Yuming PhD*,‡; Wang, Xiaoning§; Teng, Xu PhD*,‡ Author Information *Department of Physiology, Hebei Medical University, Shijiazhuang, China; †Department of Pharmacology, School of Basic Medical Sciences, Hebei University, Baoding, China; ‡Hebei Collaborative Innovation Center for Cardio-cerebrovascular Disease, Shijiazhuang, China; and §Department of Pediatrics, The Second Affiliated Hospital, Hebei Medical University, Shijiazhuang, China. Correspondence: Xiaoning Wang, Heping West Road No. 215, Shijiazhuang 050000, China (e-mail: [email protected]) or Xu Teng, Zhongshan East Road No. 361, Shijiazhuang, China 050017 (e mail: [email protected]). This work is funded by the National Natural Science Foundation of China (81100229, 81770499, 21605035) and the Natural Science Foundation of Hebei [CN] (H2016206264, H2020206350, H2013201203). The authors report no conflicts of interest. J. Sheng and W. Yipu contributed equally to this work. Journal of Cardiovascular Pharmacology 81(1):p 21-34, January 2023. | DOI: 10.1097/FJC.0000000000001369 Buy Metrics Abstract Apelin is an endogenous active peptide, playing a crucial role in regulating cardiovascular homeostasis. This study aimed to investigate the interaction between apelin and endoplasmic reticulum stress (ERS). Tunicamycin (Tm) and dithiothreitol (DTT) were used to induce ERS in the ex vivo cultured myocardium of rats. Myocardial injury was determined by the activities of lactate dehydrogenase and creatine kinase-MB in the culture medium. The protein levels of an ERS-associated molecule, apelin, and its receptor angiotensin domain type 1 receptor-associated proteins (APJ) in the myocardium were determined by western blot analysis. The level of apelin in the culture medium was determined by enzyme immunoassay. Administration of Tm and DTT triggered ERS activation and myocardial injury, and led to a decrease in protein levels of apelin and APJ, in a dose-dependent manner. Integrated stress response inhibitor, an inhibitor of eukaryotic initiation factor 2α phosphorylation that is commonly used to prevent activation of protein kinase R-like ER kinase cascades, blocked ERS-induced myocardial injury and reduction of apelin and APJ levels. The ameliorative effect of integrated stress response inhibitor was partially inhibited by [Ala]-apelin-13, an antagonist of APJ. Furthermore, apelin treatment inhibited activation of the 3 branches of ERS induced by Tm and DTT in a dose-dependent manner, thereby preventing Tm-induced or DTT-induced myocardial injury. The negative feedback regulation between ERS activation and apelin/APJ suppression might play a critical role in myocardial injury. Restoration of apelin/APJ signaling provides a potential target for the treatment and prevention of ERS-associated tissue injury and diseases. Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.