Berberine suppresses mechanical stretch-induced apoptosis and proliferation in vascular smooth muscle cells via ROS/PDI/Drp1 signaling pathway.

BACKGROUND

Vascular smooth muscle cells (VSMCs) exhibit heterogeneous responses to mechanical stretch stress (SS), with some undergoing apoptosis and others proliferating. The mechanisms underlying this differential fate decision remain unclear.

OBJECTIVE

This study investigated whether SS-induced heterogeneity in F-actin expression dictates distinct mitochondrial reactive oxygen species (ROS) responses, leading to different VSMC fates, and evaluated the therapeutic potential of the berberine (BBR).

METHODS

VSMCs were subjected to SS. F-actin heterogeneity was characterized, and mitochondrial ROS (mtROS), proliferation, and apoptosis were assessed. The involvement of the PKCα/PDI/Drp1 signaling axis was examined using pharmacological inhibitors and BBR.

RESULTS

SS induced heterogeneous mtROS production in VSMCs with varying F-actin levels. This differential ROS signaling concurrently activated the pro-proliferative mTOR/p70 pathway and the pro-apoptotic caspase-9/3 cascade via the PKCα/PDI/Drp1 axis. Importantly, BBR treatment effectively attenuated both SS-induced proliferation and apoptosis by suppressing PKCα activation and subsequent mitochondrial signaling.

CONCLUSION

Our findings reveal that F-actin heterogeneity determines VSMC fate under SS by driving distinct mitochondrial ROS responses. BBR, by counteracting these ROS-dependent pathways, emerges as a promising therapeutic strategy for managing stretch-related vascular pathologies, such as hypertension-induced atherosclerosis.