Ulinastatin protects rats with myocardial infarction by activating Nrf2/NOS pathway

S. Wang, Z.-Y. Cheng, X.-J. Chen, H.-Z. Xue

Department of Cardiovascular Surgery, The People’s Hospital of Zhengzhou University, Henan Provincial People’s Hospital, Zhengzhou, China. huanzhouxue@163.com

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• Pharmacology

OBJECTIVE: The aim of the study was to explore the pharmacological role of ulinastatin in rats with myocardium infarction (MI) and its underlying mechanism.

MATERIALS AND METHODS: Rats were randomly assigned into sham group, MI group, and ulinastatin group, with 8 rats in each group. MI model in rats was constructed and specific drug administrations were performed in each group. Electrocardiogram and hemodynamics were detected before and after animal procedures. Myocardium function in rats was accessed by determining serum levels of creatine kinase-MB (CK-MB) and lactate dehydrogenase (LDH). Hematoxylin and eosin (HE) staining was performed to detect the infarct area in rat myocardium. Terminal Deoxynucleotidyl Transferase dUTP Nick-end Labeling (TUNEL) assay was conducted to calculate the ratio of apoptotic cells in rat myocardium. Subsequently, relative oxidative stress indicators in rats were accessed, including total antioxidant capacity (T-AOC), catalase (CAT), glutathione (GSH), Superoxide Dismutase (SOD), malondialdehyde (MDA), and reactive oxygen species (ROS). Western blot was conducted to detect protein levels of nuclear factor E2-related factor 2 (Nrf2), Nuclear Factor κB (NF-Κb), heme oxygenase-1 (HO-1), and NAD(P)H:quinone oxidoreductase 1 (NQO1) in rat myocardium.

RESULTS: No significant differences in heart rate, the voltage of the QRS wave and Q-T interval were observed among rats in sham group, MI group, and ulinastatin group prior to the animal procedures. However, at the end of the animal procedures, rats in ulinastatin group showed higher heart rate and voltage of QRS wave, as well as shorter Q-T interval than those in MI group. Rats in ulinastatin group presented lower serum levels of CK-MB and LDH compared with those in MI group, whereas they did not return to baseline. Rats in ulinastatin group showed higher levels of LVSP, dP/dtmax, LVEDP, and -dP/dtmax than those in MI group. Larger infarct area was observed in MI group compared with that of sham group, whereas ulinastatin treatment remarkably reduced the infarct area. HE staining showed remarkable pathological lesions in MI rats, whereas ulinastatin group showed milder lesions in rat myocardium. TUNEL assay showed fewer TUNEL-positive cells in ulinastatin group than those of MI group. Levels of T-AOC, CAT, GSH, and SOD were remarkably higher in myocardium homogenate of MI group than sham group, whereas ulinastatin treatment significantly decreased these levels. Ulinastatin group showed less ROS accumulation and decreased MDA level in rats than those of MI group. Ulinastatin treatment upregulated Nrf2, HO-1, and NQO1, whereas downregulated NF-κB expression.

CONCLUSIONS: Ulinastatin protects MI rats by inhibiting inflammatory response through activating Nrf2/NOS pathway.

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