Lysophosphatidylcholine up‐regulates human endothelial nitric oxide synthase gene transactivity by c‐Jun N‐terminal kinase signalling pathway

Abstract

Human endothelial nitric oxide synthase (eNOS) plays a pivotal role in maintaining blood pressure homeostasis and vascular integrity. It has recently been reported that mitogen-activated protein kinases (MAPKs) are intimately implicated in expression of eNOS. However detailed mechanism mediated by them remains to be clarified. In this study, eNOS gene transactivity in human umbilical vein endothelial cells was up-regulated by stimulation of lysophosphatidylcholine (LPC). The stimulation of LPC highly activated both extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK), with differences in the dynamic processes of activation between them. Unexpectedly, p38 MAPK could not be activated by the stimulation of LPC. The activation of JNK signalling pathway by overexpression of JNK or its upstream kinase active mutant up-regulated the transactivity of eNOS significantly, but the activation of p38 signalling pathway down-regulated it largely. The inhibition of either ERK1/2 or JNK signalling pathway by kinase-selective inhibitors could markedly block the induction of the transactivity by LPC. It was observed by electrophoretic mobility shift assay that LPC stimulated both SP1 and AP1 DNA binding activity to go up. Additionally using decoy oligonucleotides proved that SP1 was necessary for maintaining the basal or stimulated transactivity, whereas AP1 contributed mainly to the increase of the stimulated transactivity. These findings indicate that the up-regulation of the eNOS gene transactivity by LPC involves the enhancement of SP1 transcription factor by the activation of JNK and ERK1/2 signalling pathways and AP1 transcription factor by the activation of JNK signalling pathway.

Eosinophil Cysteinyl Leukotriene Synthesis Mediated by Exogenous Secreted Phospholipase A2 Group X

“…In contrast, the ERK 1/2 pathway is not involved in either sPLA 2 -Xor LysoPC-induced CysLT synthesis. Although not previously identified in human eosinophils, cPLA 2 ␣ activation in other cells has been attributed to JNK (51), and LysoPC has been implicated in the activation of JNK (52,53). These results indicate that activation of p38 and JNK is involved in the sPLA 2 -X-mediated synthesis of CysLTs in eosinophils and that CysLT synthesis may be largely a consequence of the generation of lysophospholipids such as LysoPC liberated in response to sPLA 2 -X.…”

Deletion of Class A Scavenger Receptor Deteriorates Obesity-Induced Insulin Resistance in Adipose Tissue

“…LPC, a highly abundant bioactive lysoglycerophospholipid in the circulation, is involved in regulating cellular proliferation and inflammation (36)(37)(38). Sakai et al (30) have demonstrated that LPC is recognized by SR-A and required for the induction of macrophage growth.…”

Induction of Endothelial Nitric Oxide Synthase Expression by IL-17 in Human Vascular Endothelial Cells: Implications for Vascular Remodeling in Transplant Vasculopathy

“…In addition to MEK1 and NF-kB, we find that JNK is also required for the induction of eNOS expression by IL-17. JNK is known to induce eNOS expression in response to lysophosphatidylcholine in human umbilical vein ECs, but the downstream mechanisms by which this occurs remain undefined (41).…”