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

J Clin Invest. 2017 Nov 1;127(11):4075-4089. doi: 10.1172/JCI94735. Epub 2017 Oct 3.

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.

MeSH terms

  • Activating Transcription Factor 6 / genetics
  • Activating Transcription Factor 6 / metabolism
  • Animals
  • Apoptosis
  • Atherosclerosis / enzymology*
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / physiology*
  • Cells, Cultured
  • Enzyme Activation
  • Gene Expression
  • Humans
  • Liver X Receptors / metabolism
  • Macrophages / enzymology*
  • Male
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Necrosis / enzymology*
  • Phagocytosis
  • Plaque, Atherosclerotic / enzymology*
  • Plaque, Atherosclerotic / pathology
  • Signal Transduction
  • c-Mer Tyrosine Kinase / metabolism

Substances

  • Activating Transcription Factor 6
  • Atf6 protein, mouse
  • Liver X Receptors
  • Mertk protein, mouse
  • c-Mer Tyrosine Kinase
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2