Dihydromyricetin protects human umbilical vein endothelial cells from injury through ERK and Akt mediated Nrf2/HO-1 signaling pathway

Abstract

Atherosclerosis-related cardiovascular disease is the predominant cause of death worldwide. Ox-LDL-induced vascular endothelial cell injury is a major factor in the pathogenesis of atherosclerosis. Dihydromyricetin (DMY) is a flavonoid extracted from vine tea that exerts multiple pharmacological activities, including cardio-protective, anti-tumor, and anti-oxidative effects. However, it is unreported that DMY shows protective effects on ox-LDL-induced endothelial cell injury. In this study, we used an ox-LDL injured human umbilical vein endothelial cell (HUVEC) in vitro model to explore the protective effects and mechanism of DMY. HUVECs were pretreatment with DMY and then exposed to ox-LDL, the cell viability was measured. Then, the anti-oxidative enzymes were tested by commercial kits and intracellular reactive oxygen species (ROS) was measured by flow cytometry, cell apoptosis was determined by Annexin-V/PI assay and apoptosis-related proteins were detected by western blot. Our results showed that DMY pretreatment provided cytoprotective effects by suppressing ox-LDL-induced endothelial cell apoptosis, mitochondrial membrane depolarization, caspase-3 activation, and modulation of oxidative enzymes, thereby inhibiting ROS generation. The anti-oxidative and anti-apoptotic effects of DMY were abrogated by the transfection of Nrf2 siRNAs and HO-1 inhibitor ZnPP. Furthermore, DMY might activate the Nrf2/HO-1 pathway through activation of the Akt and ERK1/2 pathways, as shown by the inhibition of Nrf2/HO-1 signaling by the inhibitors PD98059 or LY294002 and the transfection of ERK, Akt siRNAs. In this study, DMY protects HUVECs from ox-LDL-induced oxidative injury by activating Akt and ERK1/2, which subsequently activates Nrf2/HO-1 signaling, thereby up-regulating antioxidant enzymes and anti-apoptotic proteins.

Inhibition of miR-153 ameliorates ischemia/reperfusion-induced cardiomyocytes apoptosis by regulating Nrf2/HO-1 signaling in rats

“…Thus, inhibition of high oxidative reactive species production can alleviate the I/R-induced damage. Importantly, activation of Nrf2/HO-1 signaling plays an important role in the inhibition of DNA damage and cell apoptosis by modulating oxidative stress [25,26]. There is evidence showing that inhibition of miR-153 protects neurons against oxygen-glucose deprivation and reoxygenation (OGD-R)induced injury by regulating Nrf2/HO-1 signaling [21].…”

Dihydromyricetin protects HUVECs of oxidative damage induced by sodium nitroprusside through activating PI3K/Akt/FoxO3a signalling pathway

“…Qin's research showed that DMY attenuated atherosclerosis through the Nrf2 signalling pathway and induced HUVEC apoptosis . Luo's found that DMY protects HUVECs from ox‐LDL‐induced oxidative injury by activating Nrf2/HO‐1 pathway by up‐regulating Akt and ERK1/2 . Zeng's study showed that DMY reduce foam cell formation via activation of LXRα‐ABCA1/ABCG1 signalling pathway .…”

“…Thereafter, 400 μL 1 × binding buffer was added and vortex briefly. The number of apoptotic cells was analysed using a flow cytometry as previously described …”

“…Liu et al found that DMY has cardioprotective effects via the PI3K/Akt signalling pathway . Luo et al reported that DMY protects HUVECs from oxidative damage by activating Akt . These results suggested that DMY could reduce atherosclerosis and suppressed the pathologically related metabolic disorders via the PI3K/Akt signalling pathway.…”

“…Tsuchiya et al found that FoxO inhibition in endothelial cells to protect mice from atherosclerosis, Knockout of FoxO in mice revealed that increased oxidative stress and accelerates atherosclerosis . The previous studies have shown that DMY play cardioprotective effects via the PI3K/Akt signalling pathway . However, whether DMY can protect HUVECs against oxidative damage via the PI3K/Akt/FoxO3a signalling pathway remains unclear.…”