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

• DOI: 10.1161/circulationaha.107.711275
• Publication Date: 2008-01-29T02:11:22Z
• Authors: Wah-Seng Lim; Jenelle M. Timmins; Tracie A. Seimon; Anthony Sadler; Frank D. Kolodgie; Renu Virmani; Ira Tabas
• Keywords: 0301 basic medicine; Mice, Knockout; 0303 health sciences; Apoptosis; Atherosclerosis; Endoplasmic Reticulum; Mice, Inbred C57BL; 03 medical and health sciences; Mice; Phosphoserine; STAT1 Transcription Factor; Receptors, LDL; Radiation Chimera; In Situ Nick-End Labeling; Macrophages, Peritoneal; Animals; Humans; Female; Calcium Signaling; Phosphorylation; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Protein Processing, Post-Translational; Bone Marrow Transplantation

Background— Macrophage apoptosis is a critical process in the formation of necrotic cores vulnerable atherosclerotic plaques. In vitro and vivo data suggest that macrophage advanced atheromata may be triggered by combination endoplasmic reticulum stress engagement type A scavenger receptor, which together induce death through rise cytosolic calcium activation toll-like receptor-4. Methods Results— Using both primary peritoneal macrophages studies vivo, we introduce signal transducer activator transcription-1 (STAT1) as necessary component stress/type receptor–induced apoptosis. We show STAT1 serine phosphorylated subjected to receptor ligands manner requiring calcium, calcium/calmodulin-dependent protein kinase II, Remarkably, was inhibited ≈80% 90% ( P <0.05) deficiency or II inhibition. nuclear Ser-P-STAT1 found macrophage-rich regions murine human atheromata. Most important, decreased 61% =0.034) plaque necrosis 34% =0.02) plaques fat-fed low density lipoprotein null Ldlr −/− mice transplanted with Stat1 bone marrow. Conclusions— for tissue These findings potentially important role STAT1-mediated progression.