Heparanase Inhibitor OGT2115 Alleviates Myocardial Hypoxia/Reoxygenation Injury in H9c2 Cells through the MAPK/ERK Pathway

Abstract

Background: Heparanase (HPSE) is an endo-beta-D-glucuronidase, and its upregulation is associated with many inflammatory diseases, such as atherosclerosis, fibrosis, and cancer. However, the role of HPSE in myocardial infarction remains unclear. Methods: Cell Counting Kit-8 (CCK8) assay was used to detect the development of the oxygen-glucose deprivation/reoxygenation (OGD/R) model and the effect of HPSE inhibitor OGT2115. Real-time quantitative PCR (RT-qPCR) and western blotting were used to detect HSPE expression in OGD/R model, the effect of HPSE inhibitor OGT2115, and the expression of cell proliferation-related protein, apoptosis-related protein, and fibrosis-related protein. The immunofluorescence assay was used to detect the expression of 5-Ethynyl-2′-Deoxyuridine (EdU) and TdT-mediated dUTP nick-end labeling (TUNEL). Enzyme-linked immunosorbent assay (ELISA) assay was used to detect the secretion of cytokines associated with the OGD/R model. Results: HPSE was highly expressed in the OGD/R model, and its inhibitor OGT2115 significantly promoted the proliferation and inhibited the apoptosis and fibrosis of H9C2 cells in the OGD/R model. Simultaneously, OGT2115 inhibited the secretion of inflammatory factors—tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and IL-8—in the OGD/R model. Further mechanistic studies demonstrated that OGT2115 could inhibit the phosphorylation of mitogen-activated protein kinases (MAPK) and extracellular signal-regulated kinase (ERK). Conclusion: HPSE inhibitor OGT2115 alleviates myocardial IR injury in H9c2 cells and inhibits the MAPK/ERK pathway, indicating that HPSE is crucial in regulating myocardial infarction, and its inhibitor OGT2115 may be a potential drug for the treatment of myocardial infarction.