Stress hyperglycemia impairs FOXK2-dependent macrophage cardiac repair after myocardial infarction
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Huizhen Lv1, Zening Liu2, Suli Feng3
1Department of Cardiology, Peking University First Hospital, Beijing 100032, China; Institute of Cardiovascular Disease, Peking University First Hospital, Beijing 100032, China; State Key Laboratory of Experimental Hematology, Tianjin Institute of Cardiology, Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Second Hospital of Tianjin Medical University, and Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin 300070, China.
Abstract:
Stress hyperglycemia (SHG) predicts poor outcomes after myocardial infarction (MI), but the underlying mechanisms remain unclear. Here, we identify FOXK2 as a key regulator of macrophage-mediated cardiac repair. FOXK2 expression was reduced in cardiac macrophages from hyperglycemic mice after MI and in peripheral blood mononuclear cells from patients with MI with SHG, whereas macrophage-specific FOXK2 deficiency aggravated cardiac injury. Under high-glucose conditions, FOXK2 was glycosylated at T552 by O-GlcNAc transferase, promoting its ubiquitin-proteasome-dependent degradation. Mass spectrometry and functional assays showed that the FOXK2T552A variant resisted hyperglycemia-induced degradation. Integrated CUT&Tag and RNA-seq analyses revealed that FOXK2 restrained pro-inflammatory cytokine expression by suppressing H3K27 acetylation. Thus, our findings identify FOXK2 as a critical regulator that supports cardiac repair during hyperglycemia, and targeting excessive FOXK2 O-GlcNAcylation may offer a therapeutic strategy for patients with MI and SHG.