The necrotic core in atherosclerotic plaques comprises cholesterol crystals and cell debris. It develops due to increased cell death and reduced removal of the dead cells by macrophages. The size of the necrotic core determines the risk for plaque rupture and cardiovascular events such as myocardial infarctions. Thus, limiting necrotic core expansion may be a promising therapeutic approach to preventing cardiovascular diseases.

• Hypoxia-inducible factor-1 promotes macrophage necroptosis by miRNA regulation.

We analyzed the metabolic mechanisms involved in the death of plaque macrophages. We found that activation of the transcription factor hypoxia-inducible factor 1 after inflammatory stimulation increases necroptotic cell death by upregulating miR-210 and downregulating miR-383. Whereas miR-210 inhibits oxidative phosphorylation by targeting 2,4-dienoyl-CoA reductase, downregulation of miR-383 impairs DNA damage repair due to derepression of poly(ADP-ribose)-glycohydrolase. Together, the opposite regulation of miR-210 and miR-383 by HIF-1 results in ATP depletion and necroptosis.

• miR-21 controls circadian apoptosis and necrotic core formation in atherosclerotic plaques

Myocardial infarctions occur more frequently in the early morning. We found that miR-21 is regulated in a circadian manner in atherosclerotic plaques. It reduced levels of miR-21 and increased apoptosis during the transition from the inactive to the active phase by derepressing the pro-apoptotic factor XAF1 in mice and humans. Therefore, a death clock in macrophages increases necrotic core formation at the beginning of the active phase due to a disbalance between apoptosis and efferocytosis.