Silencing soluble epoxide hydrolase protects against myocardial ischemia-reperfusion injury through modulation of the YAP signaling pathway and macrophage polarization.

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 and the regulation of macrophage polarization.