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Background: Prior transcriptomic analyses have illuminated a correlation between the upregulation of glycolysis, induced by oxidized low-density lipoprotein (ox-LDL), and the extent of foam cell formation. This study aimed to elucidate the impact of metabolic redirection via pyruvate dehydrogenase complex (PDH) in macrophages on the formation of foam cells and the progression of atherosclerosis. Methods: We employed a mouse model wherein bone marrow cells from either wild-type or PDK 2/4-knockout mice were transplanted into lethally irradiated LDL receptor-deficient (LDLR-/-) mice, which were subsequently maintained on a Western diet (WD) for 18 weeks. Additionally, bone marrow-derived macrophages (BMDMs) were isolated, treated with a PDK inhibitor, and then stimulated with ox-LDL for 24 hours. Results: Evaluation of atherosclerotic lesions via Oil-Red-O staining demonstrated that mice transplanted with PDK2/4-deficient bone marrow and fed a WD exhibited a reduction in plaque formation. The administration of the PDK inhibitor curtailed ox-LDL-induced M1 macrophage polarization, as evidenced by decreased Nos2 expression, alongside a notable reduction in nitric oxide production by the treated BMDMs. Conclusion: Modulation of macrophage metabolism through PDH activation can mitigate atherosclerosis by inhibiting iNOS-induced foam cell formation. These observations underscore the potential of targeting PDK as a therapeutic strategy for atherosclerosis. Disclosure J. Jeon: None. M. Kim: None. I. Lee: None.
JEON et al. (Fri,) studied this question.