Activation of JNK and transcriptional repressor ATF3/LRF1 through the IRE1/TRAF2 pathway is implicated in human vascular endothelial cell death by homocysteine.
Endothelial cell injury underlies an increased occurrence of thromboembolic vascular disease in hereditary hyperhomocysteinemia. We have previously shown that homocysteine causes activation of c-Jun NH(2)-terminal kinase (JNK) and activating transcription factor 3/liver regenerating factor 1 (ATF3/LRF1) and induces apoptosis in human umbilical vein endothelial cells (HUVECs). In this study, the activation of JNK and ATF3 in HUVECs was mediated by the endoplasmic reticulum (ER) resident transmembrane kinase IRE1alpha and beta, which sense and transduce signal of the accumulationj of unfolded proteins in the ER. Moreover, dominant negative mutants of tumor necrosis factor receptor-associated factor 2 and mitogen-activated kinase kinase 4 and 7, as well as antisense ATF3 cDNA, inhibited cell death by homocysteine. These results indicate that the activation of JNK and ATF3 through the ER stress of homocysteine plays a role in the homocysteine-induced cell death. The JNK-ATF3 pathway may be implicated in endothelial cell injury associated with hereditary hyperhomocysteinemia.
Zhang
C
C
Department of Biochemical Genetics, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
Kawauchi
J
J
Adachi
M T
MT
Hashimoto
Y
Y
Oshiro
S
S
Aso
T
T
Kitajima
S
S
D051700:Activating Transcription Factor 3; D017209:Apoptosis; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004722:Endoribonucleases; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004789:Enzyme Activation; D006710:Homocysteine / Q000494:pharmacology; D006801:Humans; D020138:Hyperhomocysteinemia / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases; D020935:MAP Kinase Signaling System; D008565:Membrane Proteins; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D011506:Proteins / Q000235:genetics / Q000502:physiology; D012097:Repressor Proteins / Q000378:metabolism; D047992:TNF Receptor-Associated Factor 2; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D014471:Umbilical Veins / Q000166:cytology
D051700:Activating Transcription Factor 3; D008565:Membrane Proteins; D011506:Proteins; D012097:Repressor Proteins; D047992:TNF Receptor-Associated Factor 2; D014157:Transcription Factors; D006710:Homocysteine; C403982:ERN2 protein, human; D017346:Protein Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D004722:Endoribonucleases