Pyruvate Carboxylase in Macrophages Aggravates Atherosclerosis by Regulating Metabolism Reprogramming to Promote Inflammatory Responses Through the Hypoxia‐Inducible Factor‐1 Signaling Pathway

Atherosclerosis (AS) is a major cause of cardiovascular diseases, driven by chronic inflammation and macrophage polarization toward a proinflammatory phenotype. Pyruvate carboxylase (PC), a mitochondrial enzyme involved in glucose metabolism, is implicated in various metabolic disorders; however, its role in AS remains unclear. This study aims to investigate the role and mechanism of PC on macrophages in AS. PC is upregulated in macrophages of humans and mice with AS. Myeloid cell-specific PC knockout mice are generated to investigate the effects of PC deletion on atherosclerotic plaque formation. Myeloid cell-specific PC deficiency mitigates high-fat diet-induced atherosclerotic lesions in apolipoprotein E knockout mice and mice injected with adeno-associated virus-PCSK9^DY. PC deletion enhances mitochondrial respiration and reduces glycolytic activity, thereby reducing reactive oxygen species overproduction and mitochondrial damage in macrophages. PC activates the hypoxia-inducible factor-1 (HIF-1) signaling pathway through macrophage metabolic reprogramming. PC induces nuclear translocation of HIF-1α in atherosclerotic aortic roots by preventing HIF-1α from proteasome degradation. HIF-1α stabilizer reverses the anti-inflammatory effect of macrophage-PC ablation in atherogenesis; however, inhibiting HIF-1α suppresses the proinflammatory macrophage phenotype induced by PC overexpression. This study indicates that macrophage PC aggravates AS through macrophage metabolic reprogramming, promoting inflammatory responses in macrophages through the HIF-1 signaling pathway.