Ulinastatin improves myocardial ischemia-reperfusion injury in rats through endoplasmic reticulum stress-induced apoptosis pathway

M.-H. Lun, X.-Y. Jin, M.-Y. Wang, Z. Cai, W. Du, Z.-Q. Huang

Department of Anesthesiology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, China. huangzq0@163.com

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• Pharmacology

OBJECTIVE: To investigate the protective role of ulinastatin (UTI) on myocardial ischemia-reperfusion (I/R) injury in rats via endoplasmic reticulum stress (ERS)-induced apoptosis pathway.
MATERIALS AND METHODS: A total of 60 rats were randomly divided into normal group (n=20), myocardial I/R model group (model group, n=20), and myocardial I/R model+UTI treatment group (treatment group, n=20). The myocardial function indicators [creatinine (Scr) and creatine kinase (CK)] were detected. Enzyme-linked immunosorbent assay (ELISA) was performed to measure serum levels of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and matrix metalloproteinase-9 (MMP-9). Meanwhile, the contents of reactive oxygen species (ROS), superoxide dismutase (SOD), and malondialdehyde (MDA) in rat left ventricular tissues were determined by ELISA as well. The cardiac function indexes were determined via magnetic resonance imaging (MRI) and echocardiography (ECG). Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling (TUNEL) staining assay was carried out to detect the apoptosis of myocardial tissues. Additionally, the expression levels of endoplasmic reticulum stress and apoptosis genes were measured through quantitative Reverse Transcription-Polymerase Chain Reaction (qRT-PCR) assay and Western blotting analysis, respectively.
RESULTS: Serum levels of alanine aminotransferase (ALT), CK, and Scr in model group were significantly higher than those in normal group (p<0.05). Besides, rats in model group had significantly lowered SOD, ejection fraction (EF, %), and fractional shortening (FS, %) than those in normal group (p<0.05). In addition, remarkably increased contents of TNF-α, IL-6, MMP-9, MDA, and ROS, as well as higher left ventricular end-diastolic diameter (LVEDd) and left ventricular end-systolic diameter (LVESd) were observed in model group in comparison with normal group (p<0.05). TUNEL staining results revealed that there were more apoptotic cells in model group than that in the other two groups (p<0.05). Expression levels of cysteine aspartic acid-specific protease 12 (Caspase-12) and glucose-regulated protein 78 (GRP78) were evidently higher in model group than those in normal group (p<0.05), while the expression level of B-cell lymphoma 2 (Bcl-2) was clearly lower in model group than that in normal group (p<0.05). UTI treatment partially reversed the above expression changes (p<0.05).
CONCLUSIONS: UTI has a protective effect against myocardial I/R injury in rats by repressing the occurrence of ERS-induced apoptosis.

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