CAMKIIγ suppresses an efferocytosis pathway in macrophages and promotes atherosclerotic plaque necrosis
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
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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Research Article Cardiology Cell biology

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

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 3

The lesions of WD-fed M-CaMKII–KO Ldlr–/– mice have less apoptosis and improved efferocytosis.

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The lesions of WD-fed M-CaMKII–KO Ldlr–/– mice have less apoptosis and i...
Aortic root lesions from the mice described in Figure 2 were assayed as follows: (A) aortic root sections were stained for TUNEL and DAPI and quantified as the percentage of TUNEL-positive cells of the total nuclei. (B) Aortic root sections were stained with an antibody specific for cleaved caspase-3 and DAPI. Data are presented as the percentage of positive cells of total nuclei. (C) Aortic root sections were costained for Mac-3 and TUNEL. Each TUNEL-positive cell was determined to be either associated with a macrophage or not associated with a macrophage, and the data are presented as the ratio of macrophage-associated apoptotic cells to free apoptotic cells. For all panels, n = 12 control and n = 11 M-CaMKII–KO mice. *P < 0.01; **P < 0.001, unpaired t test.