Krüppel-like Factor 2 (KLF2) in the Regulation of Lipid Accumulation, ROS, and Mitochondrial Functions During Foam...

Foam cell formation, a hallmark of early atherosclerotic lesion development, is closely associated with mitochondrial dysfunction and excessive reactive oxygen species (ROS) production. Disruption in mitochondrial activity leads to electron leakage, elevated ROS generation, and collapse of mitochondrial membrane potential, contributing to vascular pathogenesis. In this study, we investigated the role of Krüppel-like factor 2 (KLF2), a transcription factor known for its vasculoprotective effects, in regulating mitochondrial function during foam cell (FC) formation in RAW264.7 cells. This study demonstrates that KLF2 is decreased during FC formation of RAW264.7 cells. In contrast, lipids are highly uptaken, and both intracellular and mitochondrial ROS are increased, with enhanced mitochondrial membrane potential and mitochondrial functions during FC formation of RAW264.7 cells. To investigate the role of KLF2 in this FC formation process, we utilized both loss-of-function and gain-of-function approaches of KLF2 in RAW264.7 cells. This study demonstrates that KLF2 plays a multifaceted and protective role in preventing FC formation by regulating the uptake of lipids, reducing both intracellular and mitochondrial ROS, mitochondrial membrane potential, and mitochondrial activities, as loss-of-function of KLF2 promoted FC formation with overactivity, and gain-of-function reduced FC formation by limiting activities of all the parameters mentioned above. These findings provide mechanistic insights into the protective role of KLF2 and propose it as a potential therapeutic target for the future management of cardiovascular diseases.