The progressive loss of cardiomyocytes caused by cell death leads to cardiac dysfunction and heart failure (HF). Rapamycin has been shown to be cardioprotective in pressure‑overloaded and ischemic heart diseases by regulating the mechanistic target of rapamycin (mTOR) signaling network. However, the impact of rapamycin on cardiomyocyte death in chronic HF remains undetermined. Therefore, in the current study we addressed this issue using a rat myocardial infarction (MI)‑induced chronic HF model induced by ligating the coronary artery. Following surgery, rats were randomly divided into six groups, including the sham‑, vehicle‑ and rapamycin‑operated groups, at 8 or 12 weeks post‑MI. A period of 4 weeks after MI induction, the rats were treated with rapamycin (1.4 mg‑kg‑day) or vehicle for 4 weeks. Cardiac function was determined using echocardiography, the rats were subsequently euthanized and myocardial tissues were harvested for histological and biochemical analyses. In the cell culture experiments with H9c2 rat cardiomyocytes, apoptosis was induced using angiotensin II (100 nM; 24 h). Cardiomyocyte apoptosis and autophagy were assessed via measuring apoptosis‑ and autophagy‑associated proteins. The activities of mTOR complex 1 (mTORC1) and mTORC2 were evaluated using the phosphorylation states of ribosomal S6 protein and Akt, respectively. The activity of the endoplasmic reticulum (ER) stress pathway was determined using the levels of GRP78, caspase‑12, phospho‑JNK and DDIT3. Echocardiographic and histological measurements indicated that rapamycin treatment improved cardiac function and inhibited cardiac remodeling at 8 weeks post‑MI. Additionally, rapamycin prevented cardiomyocyte apoptosis and promoted autophagy at 8 weeks post‑MI. Rapamycin treatment for 4 weeks inhibited the mTOR and ER stress pathways. Furthermore, rapamycin prevented angiotensin II‑induced H9c2 cell apoptosis and promoted autophagy by inhibiting the mTORC1 and ER stress pathways. These results demonstrated that rapamycin reduced cardiomyocyte apoptosis and promoted cardiomyocyte autophagy, by regulating the crosstalk between the mTOR and ER stress pathways in chronic HF.

Lung cancer is considered to be one of the world's deadliest diseases, with non‑small cell lung cancer (NSCLC) accounting for 85% of all lung cancer cases. The present study aimed to investigate the role and underlying mechanisms of interleukin‑21 (IL‑21), and its receptor IL‑21R, in NSCLC. Lung tissues and blood samples of NSCLC were used to measure IL‑21, IL‑21R and programmed death 1 ligand 1 (PD‑L1) expression using ELISA, western blot and immunohistochemistry analyses. Following treatment with different doses of IL‑21, the proliferation, invasion and migration of human NSCLC cell line A549 was evaluated using a cell counting kit‑8, colony formation, Transwell and scratch wound healing assays, respectively. Additionally, IL‑21R and PD‑L1 expression in A549 cells was detected using western blot analysis and immunofluorescence. IL‑21R silencing was subsequently used to investigate its effects in cell proliferation, invasion and migration. PD‑L1, IL‑1β and tumor necrosis factor α (TNF‑α) expression were measured. Finally, Wnt/β‑catenin signaling expression was evaluated using western blot analysis following treatment with IL‑21. Cells were then treated with lithium chloride (LiCl), which is an agonist of Wnt/β‑catenin signaling, and the levels of PD‑L1, IL‑1β and TNF‑α were detected. The results revealed that IL‑21 and IL‑21R expression in the lung tissues and blood samples of patients with NSCLC were decreased, while PD‑L1 expression was increased, compared with normal tissues or healthy controls. Treatment of A549 cells with IL‑21 upregulated IL‑21R expression, downregulated PD‑L1 and inhibited cell growth and metastasis in a dose‑dependent manner. Following IL‑21R silencing, the effects of IL‑21 treatment were reversed, suggesting that IL‑21 acted on A549 cells through binding to IL‑21R. In addition, the results demonstrated that IL‑21 treatment reduced the expression levels of proteins associated with the Wnt/β‑catenin signaling, whereas activation of Wnt/β‑catenin signaling with the LiCl agonist upregulated PD‑L1, IL‑1β and TNF‑α expression. In conclusion, the IL‑21/IL‑21R axis reduced the growth and invasion of NSCLC cells via inhibiting Wnt/β‑catenin signaling and PD‑L1 expression. The present results may provide a novel molecular target for NSCLC diagnosis and therapy.