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Introduction/Backgrounds: Atherosclerosis is a cardiovascular disease initiated by dysregulated lipid homeostasis. Excessive lipid uptake of macrophage leads to forming foam cells in the intima of the arterial wall. Several transcriptome analyses in macrophage have revealed that oxidized-LDL (ox-LDL)-induced glycolysis are correlated with the degree of foam cell formation. Pyruvate dehydrogenase kinases (PDKs) regulate the activity of pyruvate dehydrogenase (PDH), gate-keeping enzyme responsible for switching the pyruvate metabolism from glycolysis to oxidative phosphorylation (OXPHOS). Here, we investigated the role of the metabolic switch by PDH in macrophages during foam cell formation. Research Question/Hypothesis: Here we tested the hypothesis that metabolic switching from glycolysis to OXPHOS in macrophage by PDK inhibition ameliorates atherosclerosis by suppressing iNOS-induced foam cell formation. Goals/Aims: The aim to asses a potential therapeutic approach for the management of atherosclerosis by inhibition of PDK Methods/Approach: Bone marrow cells from wild-type or PDK X-deficient mice were transplanted into irradiated LDLR-/- mice, followed by western diet (WD) for 18 weeks. Mouse bone marrow-derived macrophages (BMDMs) were treated with PDK inhibitor, followed by activation with ox-LDL for 24hr. Results/Data: Oil red O staining of the whole aorta and heart valve revealed that PDK X-deficient bone marrow transplanted WD-fed LDLR-/- mice significantly reduced atherosclerotic plaques. PDK inhibitor hampered ox-LDL-induced M1 polarization, confirmed by Nos2 expression. Moreover, PDK inhibitor-treated BMDM showed a marked decrease in nitric oxide production. Conclusion: These findings suggest that PDH-mediated metabolic switch ameliorates atherosclerosis by suppressing iNOS-induced foam cell formation. Our data provide evidence that inhibition of PDK may be a promising therapeutic agent for atherosclerosis.
Sinam et al. (Wed,) studied this question.
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