sVEGFR3 alleviates myocardial ischemia/reperfusion injury through regulating mitochondrial homeostasis and immune cell infiltration.

Abstract

Recent studies have suggested that sVEGFR3 is involved in cardiac diseases by regulating lymphangiogenesis; however, results are inconsistent. The aim of this study was to investigate the function and mechanism of sVEGFR3 in myocardial ischemia/reperfusion injury (MI/RI). sVEGFR3 effects were evaluated in vivo in mice subjected to MI/RI, and in vitro using HL-1 cells exposed to oxygen-glucose deprivation/reperfusion. Echocardiography, TTC-Evans blue staining, ELISA, electron microscopy, immunofluorescence, western blotting, and flow cytometry were used to investigate whether sVEGFR3 attenuates I/R injury. Transcriptome sequencing was used to investigate the downstream mechanism of sVEGFR3. Results showed that, in vivo, sVEGFR3 pretreatment reduced cardiac dysfunction, infarct area, and myocardial injury indicators by reducing ROS production, AIF expression, and apoptosis. In vitro, sVEGFR3 restored mitochondrial homeostasis by stabilizing the mitochondrial membrane potential (MMP) and preventing the opening of mitochondrial permeability transition pores (mPTP). And sVEGFR3 inhibits mitochondrial apoptosis through the Ras/MEK/ERK pathway. Furthermore, I/R injury increased the proportion of M1 macrophages and CD4 + T cells in myocardial tissue, as well as serum IFN-γ and TNF-α levels, whereas sVEGFR3 treatment attenuated these effects. sVEGFR3 attenuates MI/RI by regulating mitochondrial homeostasis and immune cell infiltration, and reduces intrinsic ROS-mediated mitochondrial apoptosis via the Ras/MEK/ERK pathway.