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CAMKIIγ suppresses an efferocytosis pathway in macrophages and promotes atherosclerotic plaque necrosis
Amanda C. Doran, … , Alan R. Tall, Ira Tabas
Amanda C. Doran, … , Alan R. Tall, Ira Tabas
Published October 3, 2017
Citation Information: J Clin Invest. 2017;127(11):4075-4089. https://doi.org/10.1172/JCI94735.
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Research Article Cardiology Cell biology

CAMKIIγ suppresses an efferocytosis pathway in macrophages and promotes atherosclerotic plaque necrosis

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Abstract

Atherosclerosis is the underlying etiology of cardiovascular disease, the leading cause of death worldwide. Atherosclerosis is a heterogeneous disease in which only a small fraction of lesions lead to heart attack, stroke, or sudden cardiac death. A distinct type of plaque containing large necrotic cores with thin fibrous caps often precipitates these acute events. Here, we show that Ca2+/calmodulin-dependent protein kinase γ (CaMKIIγ) in macrophages plays a major role in the development of necrotic, thin-capped plaques. Macrophages in necrotic and symptomatic atherosclerotic plaques in humans as well as advanced atherosclerotic lesions in mice demonstrated activation of CaMKII. Western diet–fed LDL receptor–deficient (Ldlr–/–) mice with myeloid-specific deletion of CaMKII had smaller necrotic cores with concomitantly thicker collagen caps. These lesions demonstrated evidence of enhanced efferocytosis, which was associated with increased expression of the macrophage efferocytosis receptor MerTK. Mechanistic studies revealed that CaMKIIγ-deficient macrophages and atherosclerotic lesions lacking myeloid CaMKIIγ had increased expression of the transcription factor ATF6. We determined that ATF6 induces liver X receptor-α (LXRα), an Mertk-inducing transcription factor, and that increased MerTK expression and efferocytosis in CaMKIIγ-deficient macrophages is dependent on LXRα. These findings identify a macrophage CaMKIIγ/ATF6/LXRα/MerTK pathway as a key factor in the development of necrotic atherosclerotic plaques.

Authors

Amanda C. Doran, Lale Ozcan, Bishuang Cai, Ze Zheng, Gabrielle Fredman, Christina C. Rymond, Bernhard Dorweiler, Judith C. Sluimer, Joanne Hsieh, George Kuriakose, Alan R. Tall, Ira Tabas

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Figure 1

Expression of p-CaMKII is increased in advanced and symptomatic atherosclerotic lesions of humans and mice.

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Expression of p-CaMKII is increased in advanced and symptomatic atherosc...
(A) Human carotid specimens were obtained at time of endarterectomy from asymptomatic (Asympt) or symptomatic (Sympt) subjects with recent TIA/stroke. Fixed sections were costained for p-CaMKII (green), CD68 (red), and DAPI (nuclei; blue). Sections stained with isotype control antibodies for p-CaMKII and CD68 showed absence of signal. p-CaMKII staining was quantified as MFI within CD68+ cells. Data are presented relative to the average value obtained for the asymptomatic subjects’ specimens (n = 7 asymptomatic and 5 symptomatic subjects, 2 slides per patient). Scale bar: 500 μm. (B) Left: adjacent sections from the human carotid endarterectomy specimens in panel A were stained with H&E, and necrotic area was quantitated. Right: relationship between necrotic area and p-CaMKII fluorescence intensity in macrophages per low power field (LPF) was plotted (r2 = 0.6195, P = 0.0024). Correlation coefficient (r2) and P values were calculated using Pearson product-moment correlation analysis. (C) Sections of human coronary arteries obtained from individual subjects at autopsy were classified as PIT or TCFA and stained and quantified as above. Data are presented relative to the average value obtained for the PIT specimens (n = 5 subjects in each group, 2 slides per patient). Scale bar: 250 μm. (D) Frozen aortic root sections from 8-week and 16-week WD-fed Ldlr–/– mice were costained for p-CaMKII (green), Mac-3 (red), and DAPI (blue). p-CaMKII staining was quantified as MFI within Mac-3+ cells. Data are presented relative to the average value obtained for the 8-week specimens (n = 5 mice in each group, 2 slides per mouse). Scale bar: 150 μm. *P < 0.05, **P < 0.01, Mann-Whitney U test.
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