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*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

52 Citations (Web of Science)

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

Original languageEnglish
Pages (from-to)4075-4089
Number of pages15
JournalJournal of Clinical Investigation
Volume127
Issue number11
DOIs
Publication statusPublished - 1 Nov 2017

Keywords

  • ENDOPLASMIC-RETICULUM STRESS
  • APOPTOTIC CELL ACCUMULATION
  • C/EBP HOMOLOGOUS PROTEIN
  • APOE-DEFICIENT MICE
  • LIVER-X-RECEPTOR
  • KINASE-II
  • LIPID MEDIATORS
  • PHAGOCYTOSIS
  • INFLAMMATION
  • RESOLUTION

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