Liraglutide reprograms vascular smooth muscle cell metabolism to suppress extracellular matrix remodeling in diabetic...

Metabolic reprogramming contributes to vascular dysfunction in diabetic atherosclerosis, but the mechanisms linking hyperglycemia-induced metabolic alterations to extracellular matrix remodeling in vascular smooth muscle cells remain incompletely understood. This study investigated whether liraglutide modulates vascular smooth muscle cell metabolism and plaque remodeling under diabetic conditions.

Primary vascular smooth muscle cells were exposed to normal glucose, high glucose, or high glucose plus liraglutide. Cellular bioenergetics, mitochondrial function, oxidative stress, extracellular matrix remodeling, and AMPK/PGC-1α, mTOR, and HIF-1α signaling were assessed. In vivo, diabetic ApoE^-/- mice were treated with liraglutide for 12 weeks, followed by evaluation of metabolic parameters, aortic root plaque burden, lipid deposition, collagen content, and plaque-associated signaling markers.

High glucose impaired mitochondrial respiration, enhanced glycolysis, reduced mitochondrial membrane potential, increased mitochondrial reactive oxygen species, and promoted mitochondrial fragmentation and extracellular matrix remodeling in vascular smooth muscle cells. Liraglutide restored mitochondrial function, activated AMPK/PGC-1α signaling, suppressed mTOR activation and HIF-1α accumulation, reduced collagen I, MMP-2, and MMP-9 expression, and partially restored elastin levels. In diabetic ApoE^-/- mice, liraglutide improved systemic metabolic parameters, reduced atherosclerotic plaque burden and lipid accumulation, increased plaque collagen content, restored plaque p-AMPK expression, and reduced HIF-1α and MMP-9 expression.

Liraglutide attenuates hyperglycemia-induced metabolic reprogramming and extracellular matrix remodeling in vascular smooth muscle cells and improves plaque stability in diabetic atherosclerosis. These effects are associated with restoration of AMPK/PGC-1α signaling, inhibition of mTOR activation, suppression of HIF-1α accumulation, and improved mitochondrial homeostasis.