Backgrounds Foam cell (FC) formation is a hallmark of early atherosclerosis, driven by dysregulated lipid uptake, impaired mitochondrial clearance, and metabolic reprogramming in myeloid cells. However, the precise role of KLF2 in modulating autophagy, mitophagy, and glycolysis during FC formation remains inadequately explored.
Methods This study uncovers the critical regulatory role of Krüppel-like factor 2 (KLF2) during foam cell formation of myeloid cells (RAW264.7) using quantitative real-time PCR, immunocytochemistry, confocal microscopy, and glycolysis stress test methods.
Results Exposure to oxidized low-density lipoprotein (ox-LDL) suppressed autophagy and mitophagy markers in myeloid cells. It also increased glycolytic activity in myeloid cells during FC formation. A well-known chemical suppressor of KLF2, GGPP, further amplified these changes, highlighting the importance of endogenous KLF2 in maintaining mitochondrial health and metabolic functions during formation. To confirm the role of KLF2 in this process, when a chemical inducer of KLF2, GGTI298, was added during FC formation, it restored autophagic and mitophagic machinery, including the expression of Beclin1, LC3B, Parkin, and Pink1, and reversed the abnormal increase in glycolysis during FC formation.
Conclusion These findings demonstrate that KLF2 is a key transcriptional regulator that limits FC formation by preserving mitochondrial health and reducing excessive glycolysis. Furthermore, these results suggest KLF2 could be a target for future development of therapeutics for preventing FC formation, which is an early event in atherosclerosis development.
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