Signal transducer and activator of transcription-1 is critical for apoptosis in macrophages subjected to endoplasmic reticulum stress in vitro and in advanced atherosclerotic lesions in vivo.
BACKGROUND
Macrophage apoptosis is a critical process in the formation of necrotic cores in vulnerable atherosclerotic plaques. In vitro and in vivo data suggest that macrophage apoptosis in advanced atheromata may be triggered by a combination of endoplasmic reticulum stress and engagement of the type A scavenger receptor, which together induce death through a rise in cytosolic calcium and activation of toll-like receptor-4.


RESULTS
Using both primary peritoneal macrophages and studies in advanced atheromata in vivo, we introduce signal transducer and activator of transcription-1 (STAT1) as a critical and necessary component of endoplasmic reticulum stress/type A scavenger receptor-induced macrophage apoptosis. We show that STAT1 is serine phosphorylated in macrophages subjected to type A scavenger receptor ligands and endoplasmic reticulum stress in a manner requiring cytosolic calcium, calcium/calmodulin-dependent protein kinase II, and toll-like receptor-4. Remarkably, apoptosis was inhibited by approximately 80% to 90% (P<0.05) by STAT1 deficiency or calcium/calmodulin-dependent protein kinase II inhibition. In vivo, nuclear Ser-P-STAT1 was found in macrophage-rich regions of advanced murine and human atheromata. Most important, macrophage apoptosis was decreased by 61% (P=0.034) and plaque necrosis by 34% (P=0.02) in the plaques of fat-fed low density lipoprotein receptor null Ldlr-/- mice transplanted with Stat1-/- bone marrow.


CONCLUSIONS
STAT1 is critical for endoplasmic reticulum stress/type A scavenger receptor-induced apoptosis in primary tissue macrophages and in macrophage apoptosis in advanced atheromata. These findings suggest a potentially important role for STAT1-mediated macrophage apoptosis in atherosclerotic plaque progression.
Lim
Wah-Seng
WS
Department of Medicine, Columbia University, 630 W 168th St, New York, NY 10032, USA.
Timmins
Jenelle M
JM
Seimon
Tracie A
TA
Sadler
Anthony
A
Kolodgie
Frank D
FD
Virmani
Renu
R
Tabas
Ira
I
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology*; D016026:Bone Marrow Transplantation; D020013:Calcium Signaling; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000502:physiology; D004721:Endoplasmic Reticulum / Q000502:physiology*; D005260:Female; D006801:Humans; D020287:In Situ Nick-End Labeling; D017737:Macrophages, Peritoneal / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D011828:Radiation Chimera; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D050794:STAT1 Transcription Factor / Q000032:analysis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051117:Scavenger Receptors, Class A / Q000187:drug effects / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000502:physiology
D011973:Receptors, LDL; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D051117:Scavenger Receptors, Class A; C494080:Stat1 protein, mouse; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D010768:Phosphoserine; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2