Lysophosphatidylcholine induces cytotoxicity/apoptosis and IL-8 production of human endothelial cells: Related mechanisms

Abstract

Increased levels of oxidized low-density lipoprotein oxLDL) are shown to elevate the risk of cardiovascular diseases such as atherosclerosis, thrombosis, stroke, and myocardial infarction. This is possibly due to the toxic effects of oxLDLs on vascular cells. Various oxLDLs including lysophosphatidylcholine (LPC) and 7-ketocholesterol injure vascular endothelial cells and stimulate inflammatory reaction. However the toxicity of LPC on endothelial cells is not clear. In this study, human endothelial cells were exposed to LPC. Cytotoxicity was measured by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay. Propidium iodide (PI) staining or PI/Annexin V dual staining flow cytometry were used to determine cell cycle progression and apoptosis. Reactive oxygen species (ROS) level was analyzed by DCFH-DA labeling flow cytometry. RNA and protein expression of endothelial cells was studied by reverse transcriptase-polymerase chain reaction and western blotting. IL-8 secretion was measured by enzyme-linked immunosorbant assay. LPC showed cytotoxicity to endothelial cells (>50 µg/ml). LPC induced cell cycle arrest and apoptosis with concomitant inhibition of cdc2 and cyclin B1 expression. LPC stimulated intracellular ROS production and ATM/Chk2, ATR/Chk1 and Akt activation. IL-8 expression and secretion in endothelial cells were induced by LPC. LPC-induced apoptosis, and IL-8 expression/secretion was attenuated by LY294002, a PI3K/Akt inhibitor. These results reveal that LPC is involved in the pathogenesis of atherosclerosis and vascular diseases by stimulation of inflammation and injury to endothelial cells. These events are related to ROS, ATM/Chk2, ATR/Chk2 and PI3K/Akt signaling. Understanding the toxic mechanisms of LPC is useful for future prevention and treatment atherosclerosis.

Lysophosphatidylcholine‐induced cytotoxicity and protection by heparin in mouse brain bEND.3 endothelial cells

“…In HUVEC, LPC causes apoptosis, generation of ROS and caspase‐3 activation, which could be inhibited by antioxidants and superoxide dismutase . In two recent reports, LPC has also been shown to trigger ROS production in HUVEC . However, in this work, LPC did not stimulate ROS formation in bEND.3 cells at all, and LPC‐inflicted cell death could not be rescued by ascorbic acid ( Figure ).…”

Lysophosphatidylcholine Induces NLRP3 Inflammasome-Mediated Foam Cell Formation and Pyroptosis in Human Monocytes and Endothelial Cells

“…Chang and colleagues demonstrated that LPC induces cytotoxicity/apoptosis and IL-8 production in human endothelial cells via mechanisms dependent on ROS, ATM/Chk2, ATR/Chk2, and PI3K/Akt signaling (67). Pyroptosis is a form of proinflammatory cell death and (68) can be mediated by inflammasome-dependent caspase-1 activation (69) or caspase-11 (70), which is responsible for the cleavage and/or maturation of gasdermin D (GSDMD) and membrane pore formation (71), IL-1β (72), IL-18 (73), HMGB1 (74), and LDH release (75).…”

Longitudinal Intravital Microscopy Reveals Axon Degeneration Concomitant With Inflammatory Cell Infiltration in an LPC Model of Demyelination

“…LPC plasmatic concentration must be regulated physiologically because 100-µM doses already turn out toxic for most cell types, from OLs (Plemel et al, 2018) to endothelial cells (Akerele and Cheema, 2015). Endogenous LPC is indeed likely involved in atherosclerosis (Chang et al, 2017) and affects the occurrence of major depressive disorders (Liu et al, 2016).…”