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(Circulation. 2008;117:940-951.)
© 2008 American Heart Association, Inc.

Molecular Cardiology

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

Wah-Seng Lim, PhD; Jenelle M. Timmins, PhD; Tracie A. Seimon, PhD; Anthony Sadler, PhD; Frank D. Kolodgie, PhD; Renu Virmani, MD; Ira Tabas, MD, PhD

From the Departments of Medicine (W.L., J.M.T., T.A.S., I.T.), Pathology and Cell Biology (I.T.), and Physiology and Cellular Biophysics (I.T.), Columbia University, New York, NY; Monash Institute of Medical Research (A.S.), Monash University, Victoria, Australia; and CVPath Institute Inc (F.D.K., R.V.), Gaithersburg, Md.

Correspondence to Ira Tabas, MD, PhD, Department of Medicine, Columbia University, 630 W 168th St, New York, NY 10032. E-mail iat1{at}columbia.edu

Received April 25, 2007; accepted November 15, 2007.

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 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.

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CLINICAL PERSPECTIVE

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