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

Article

关键词: UNFOLDED PROTEIN RESPONSE;    SERINE PHOSPHORYLATION;    PATTERN-RECOGNITION;    SCAVENGER RECEPTORS;    KINASE-II;    EXPRESSION;    STAT1;    INTERLEUKIN-10;    PLAQUES;    DEATH;   

DOI  :  10.1161/CIRCULATIONAHA.107.711275

来源: SCIE

【 摘 要 】

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. Methods and 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 approximate to 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.

【 授权许可】

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