Interplay Between AMPK Signaling and Matrix Metalloproteinases in Atherosclerotic Plaque Stability

Atherosclerotic plaque rupture is a major contributor to acute coronary syndromes and ischemic stroke, with extracellular matrix degradation and fibrous-cap thinning being critical determinants of plaque vulnerability. This review summarizes current evidence linking AMPactivated Protein Kinase (AMPK) signaling to Matrix Metalloproteinase (MMP)-mediated regulation of atherosclerotic plaque stability. Experimental and clinical studies examining the roles of AMPK in inflammatory signaling, oxidative stress, autophagy, and vascular cell function were evaluated. Available evidence suggests that metabolic dysfunction and chronic inflammation promote MMP expression and activity, thereby contributing to the degradation of collagen and elastin within the extracellular matrix. AMPK activation may attenuate MMP expression and activity through modulation of NF-κB and Mitogen-Activated Protein Kinase (MAPK) signaling, oxidative stress, and autophagy. Furthermore, the AMPK–MMP axis appears to exert cell-specific effects in endothelial cells, vascular smooth muscle cells, and macrophages, highlighting its complex role in vascular inflammation and plaque remodeling. Overall, AMPK may act as an important metabolic and signaling regulator that integrates metabolic homeostasis, inflammatory responses, and extracellular matrix remodeling to support plaque integrity. Modulation of AMPK signaling and selected MMPs may therefore represent a potential therapeutic approach for stabilizing vulnerable atherosclerotic plaques and reducing the risk of cardiovascular and cerebrovascular events.