# Krüppel-like Factor 2 (KLF2) in the Regulation of Lipid Accumulation, ROS, and Mitochondrial Functions During Foam Cell Formation in RAW264.7 Cells

## TL;DR

This study shows that KLF2 helps prevent foam cell formation by reducing lipid uptake and mitochondrial stress, suggesting it could be a target for treating heart disease.

## Contribution

The study reveals KLF2's protective role in foam cell formation through regulation of lipid uptake and mitochondrial function.

## Key findings

- KLF2 deficiency increases foam cell formation with elevated ROS and mitochondrial activity.
- KLF2 overexpression reduces lipid uptake and mitochondrial dysfunction during foam cell formation.
- KLF2 acts as a potential therapeutic target for cardiovascular diseases.

## Abstract

This study defines the role of KLF2, which decreases during foam cell (FC) formation of myeloid cells. We found that lipids are rapidly taken up, and both intracellular and mitochondrial ROS levels increased during FC formation. Mitochondria undergo depolarization and enter a state of dysfunctional hyperactivity. To examine KLF2′s role in this process, we employed both loss-of-function and gain-of-function approaches in RAW264.7 cells. The study demonstrates that KLF2 plays a multifaceted and protective role in preventing FC formation by regulating lipid uptake and reducing both intracellular and mitochondrial ROS, mitochondrial membrane potential, and mitochondrial activity. Loss of KLF2 results in increased FC formation with overactivity, while gain-of-function reduces FC formation by limiting these parameters. These findings provide mechanistic insights into the protective role of KLF2 and suggest it as a potential therapeutic target for future cardiovascular disease management.

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.