Abstract

The objective of this study was to examine the impact of soluble epoxide hydrolase (sEH) on myocardial ischemia–reperfusion (I/R) injury and elucidate the underlying mechanisms. Enzyme-linked immunosorbent assay (ELISA) results revealed that, compared to the Sham group, the concentration of epoxyeicosatrienoic acids (EETs) was significantly reduced in the myocardial tissue of I/R mice, while soluble epoxide hydrolase (sEH) enzyme activity and 14,15-dihydroxyeicosatrienoic acid (14,15-DHET) levels were markedly elevated. Echocardiography, Evans blue/TTC staining, hematoxylin–eosin (HE) staining, and associated indicators demonstrated that the silencing of sEH enhanced cardiac function and ameliorated myocardial tissue damage, leading to a reduction in myocardial infarction size and myocardial cell apoptosis in I/R mice. Furthermore, there was a decrease in the expression of lactate dehydrogenase (LDH), creatine kinase (CK), creatine kinase isoenzyme (CK-MB), and cardiac troponin I (cTnI). Silencing sEH attenuated the inflammatory response induced by I/R injury. It also reduced the release of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1β. Additionally, it modulated macrophage polarization towards the M2 phenotype. Silencing sEH promoted the YAP signaling pathway, enhancing YAP, CTGF, and Cyr61 expression in I/R injured mouse myocardial tissues and H/R treated cardiomyocytes. Overexpression of YAP can reduce myocardial cell damage induced by H/R, as evidenced by increased cell viability, decreased apoptosis, and lower levels of myocardial injury markers (cTn-I, CK-MB, H-FABP). Additionally, silencing sEH influenced macrophage polarization via the YAP pathway, decreasing TNF-α and IL-6, increasing IL-10, and shifting from M1 to M2 macrophages. Verteporfin treatment reversed these effects. In conclusion, silencing sEH protects against myocardial I/R injury, and the underlying mechanism may be associated with the modulation of YAP signaling pathway activity a