Inhibition of the ox-LDL-Induced Pyroptosis by FGF21 of Human Umbilical Vein Endothelial Cells Through the TET2-UQCRC1-ROS Pathway.

Fibroblast growth factor 21 (FGF21) is a hormone-like member of the FGF family that is associated with cell death in atherosclerosis. However, its underlying mechanisms remain unclear. In this study, the effect of FGF21 on endothelial cell pyroptosis and its potential mechanisms were investigated. Results showed that FGF21 inhibits oxidized low-density lipoprotein (ox-LDL)-induced pyroptosis and related molecular expression in human umbilical vein endothelial cells (HUVECs). Mitochondrial function was damaged by ox-LDL and restored by FGF21. A mechanism proved that ubiquinol cytochrome c reductase core protein I (UQCRC1) was downregulated by ox-LDL and upregulated by FGF21. Further, the silencing of UQCRC1 aggravated HUVEC pyroptosis and impaired mitochondrial function and reactive oxygen species (ROS) production. Moreover, Tet methylcytosine dioxygenase (TET2) was involved in the regulation of UQCRC1 expression and pyroptosis. In summary, FGF21 inhibited ox-LDL-induced HUVEC pyroptosis through the TET2-UQCRC1-ROS pathway.

miR-23b-3p and miR-125b-5p downregulate apo(a) expression by targeting Ets1 in HepG2 cells.

High concentrations of plasma lipoprotein(a) [Lp(a)] have been inferred to be an independent risk factor for cardiovascular and cerebrovascular diseases, such as coronary artery diseases, restenosis, and stroke. Apolipoprotein(a) [apo(a)] is one of the most important components of Lp(a) and contributes greatly to the increased concentration of plasma Lp(a). As a critical positive transacting factor of apo(a) gene, Ets1 has been proven as a target gene of several miRNAs, such as miR-193b, miR-125b-5p, miR-200b, miR-1, and miR-499. In this study, a series of experiments on miRNAs and relative miRNAs inhibitor delivered HepG2 cells were conducted, and two miRNAs that downregulate the apo(a) by targeting the 3'-UTR of Ets1 were identified. Results showed that apo(a) and Ets1 were differentially expressed in SMMC7721 and HepG2 cell lines. Meanwhile, apo(a) and Ets1 were inversely correlated with several hepatic endogenous miRNAs, such as miR-125b-5p, miR-23b-3p, miR-26a-5p, and miR-423-5p, which were predicted to bind to Ets1. Results show that miR-125b-5p and miR-23b-3p mimics could inhibit the synthesis of apo(a) by directly targeting Ets1 in HepG2, thereby reducing the plasma Lp (a) concentration.

Vitamin C down-regulate apo(a) expression via Tet2-dependent DNA demethylation in HepG2 cells.

Lipoprotein(a)[Lp(a)] is a risk factor for coronary heart diseases. However, the metabolism of this protein remains poorly understood. Efficient and specific drugs that can decrease high plasma levels of Lp(a) have not been developed yet. Vitamin C is responsible for maintaining the catalytic activity of a group of iron and 2-oxoglutarate (2OG)-dependent dioxygenases and induces the generation of 5-hydroxymethylcytosine (5hmC) via Ten-eleven translocation (Tet) dioxygenases. In addition, It has been reported vitamin C deficiency induces atherosclerosis and increases Lp(a) and apo(a) plasma levels in Lp(a)+ mice. However, the mechanism is still unclear. In this study, we investigated the effects of vitamin C on apo(a) expression and the possible molecular mechanism of vitamin C that influences apolipoprotein(a) [apo(a)] biosynthesis in HepG2 cells. Results showed that vitamin C significantly inhibited the expression and secretion levels of apo(a). Vitamin C can also increase ELK1 expression and hydroxymethylation of ELK1 promoter and the globle DNA in HepG2 cells. In addition, the effects of vitamin C inhibiting the apo(a) expression were attenuated by ELK1siRNA and Tet2siRNA. These results suggested vitamin C down-regulate apo(a) expression via Tet2-dependent DNA demethylation in HepG2 cells.

H2 S inhibits apo(a) expression and secretion through PKCα/FXR and Akt/HNF4α pathways in HepG2 cells.

Lipoprotein(a) [Lp(a)] is a strong genetic risk factor for coronary heart diseases. However, the metabolism of this protein remains poorly understood. Efficient and specific drugs that can decrease high plasma levels of Lp(a) have not been developed yet. Hydrogen sulfide (H2 S), a member of the gas transmitter family, performs important biological actions, including protection against cardiovascular diseases and maintenance of the lipid metabolism equilibrium in hepatocytes and adipocytes. In this study, we investigated the possible molecular mechanism of H2 S that influences apolipoprotein(a) [apo(a)] biosynthesis. We also determined the effects of H2 S on apo(a) expression and secretion in HepG2 cells as well as the underlying mechanisms. Results showed that H2 S significantly inhibited the expression and secretion levels of apo(a). These effects were attenuated by the PKCα inhibitor and FXR siRNA. H2 S also reduced HNF4α expression and enhanced FXR expression. The Akt inhibitor partially reversed H2 S-induced inhibition of apo(a) and HNF4α expression and apo(a) secretion. This study reveals that H2 S suppressed apo(a) expression and secretion via the PKCα-FXR and PI3K/Akt-HNF4α pathways.

Ox-Lp(a) transiently induces HUVEC autophagy via an ROS-dependent PAPR-1-LKB1-AMPK-mTOR pathway.

Oxidised lipoprotein(a) [oxLp(a)] is considered as a more potent arteriosclerotic factor than native Lp(a). However, the molecular mechanisms underlying this potency remain unclear. Reactive oxygen species (ROS) possibly act as intracellular second messengers that participate in autophagy stimulation. In this study, the effect of oxLp(a) on endothelial cell autophagy was determined. The mechanism and effect of autophagy on endothelial cells were also investigated. Results showed that oxLp(a) could induce autophagy depending on the generation of cellular ROS. Superoxide dismutase, an antioxidant, could inhibit oxLp(a)-induced autophagy in human umbilical vascular endothelial cells. Furthermore, poly(adenosine diphosphate-ribose) polymerase-1 (PARP-1)-liver kinase B1 (LKB1)-adenosine monophosphate-activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR) and LKB1-AMPK-mTOR pathways are involved in oxLp(a)-induced autophagy. These pathways are also dependent on ROS. Thus, oxLp(a) induced autophagy via LKB1-AMPK-mTOR and PAPR-1-LKB1-AMPK-mTOR pathways, which are dependent on ROS generation.