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CAMKII? 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 ? (CaMKII?) 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 CaMKII?-deficient macrophages and atherosclerotic lesions lacking myeloid CaMKII? had increased expression of the transcription factor ATF6. We determined that ATF6 induces liver X receptor-? (LXR?), an Mertk-inducing transcription factor, and that increased MerTK expression and efferocytosis in CaMKII?-deficient macrophages is dependent on LXR?. These findings identify a macrophage CaMKII?/ATF6/LXR?/MerTK pathway as a key factor in the development of necrotic atherosclerotic plaques.

SUBMITTER: Doran AC 

PROVIDER: S-EPMC5663361 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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

Doran Amanda C AC   Ozcan Lale L   Cai Bishuang B   Zheng Ze Z   Fredman Gabrielle G   Rymond Christina C CC   Dorweiler Bernhard B   Sluimer Judith C JC   Hsieh Joanne J   Kuriakose George G   Tall Alan R AR   Tabas Ira I  

The Journal of clinical investigation 20171003 11


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 necr  ...[more]

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