Abstract
Recent studies have suggested that sVEGFR-3 is involved with cardiac disease by regulating lymphangiogenesis; however, results are inconsistent. The purpose of this study was to investigate the role and mechanism of sVEGFR-3 in myocardial ischemia/reperfusion injury (MI/RI). Plasma sVEGFR-3 levels were measured in patients with heart valve disease (HVD). sVEGFR-3 effects were evaluated in vivo in mice subjected to MI/RI, and in vitro using HL-1 cells exposed to hypoxia/reoxygenation. Echocardiography, TTC-Evans blue staining, ELISA, electron microscopy, immunofluorescence, Western blotting, and flow cytometry were used to investigate if sVEGFR3 attenuated I/R injury. TMT-based proteomics analysis was used to investigate the downstream mechanism of sVEGFR3. Results showed that plasma sVEGFR-3 levels were decreased in HVD patients compared to heathy control subjects. In patients undergoing cardiopulmonary bypass (CPB), sVEGFR-3 was significantly increased at 2 hours after release of the aortic cross-clamp and decreased slightly at 24 hours. In vivo, sVEGFR-3 pretreatment reduced cardiac dysfunction, infarct area, and myocardial injury indicators by reducing ROS production, apoptosis, and AIF expression. In vitro, sVEGFR-3 restored mitochondrial homeostasis by stabilizing the mitochondrial membrane potential (MMP) and preventing the opening of mitochondrial permeability transition pores (mPTP). And sVEGFR-3 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 sVEGFR-3 treatment attenuated these effects. sVEGFR-3 attenuates myocardial I/R injury by regulating mitochondrial homeostasis and immune cell infiltration, and reduces intrinsic ROS-mediated mitochondrial apoptosis via the Ras/MEK/ERK pathway.