Hyperglycemia worsens smooth muscle foam cell formation through PI3Kγ-dependent defective autophagy

Diabetic patients are particularly susceptible to cardiovascular complications following atherosclerosis. Uncontrolled glycemia leads to arterial dysfunction, potentially responsible for these increased risks. While the impact of hyperglycemia on endothelial cells and macrophages is well documented, its role in smooth muscle cells (SMCs) remains underexplored. In vivo , using a wire injury-based accelerated atherosclerosis mouse model, we showed that hyperglycemia increased lipid loading of SMCs. In vitro , we further confirmed this important finding in human primary SMCs exposed to elevated glucose concentrations. This effect originated from a defective autophagy, since autophagy activators prevented lipid droplet accumulation in SMCs. Furthermore, blocking phosphoinositide-3-kinase gamma (PI3Kγ) activity prevented the formation of foam SMCs, by restoring autophagy linked to the nuclear translocation of the transcription factor EB (TFEB), arguing for a major role of this kinase in this process. Understanding the disruption of SMC homeostasis in a hyperglycemic environment holds the promise of a new therapeutic approach, involving PI3Kγ inhibitors, to prevent major cardiovascular diseases (CVD) and their recurrences in diabetic patients.