AMPK alpha inactivation destabilizes atherosclerotic plaque in streptozotocin-induced diabetic mice through AP-2 alpha/miRNA-124 axis

Diabetes mellitus is one of risk factors of cardiovascular diseases including atherosclerosis. Whether and how diabetes promotes the formation of unstable atherosclerotic plaque is not fully understood. Here, we show that streptozotocin-induced type 1 diabetes reduced collagen synthesis, leading to the formation of unstable atherosclerotic plaque induced by collar placement around carotid in apolipoprotein E knockout (Apoe(-/-)) mice. These detrimental effects of hyperglycemia on plaque stability were reversed by metformin in vivo without altering the levels of blood glucose and lipids. Mechanistically, we found that high glucose reduced the phosphorylated level of AMP-activated protein kinase alpha (AMPK alpha) and the transcriptional activity of activator protein 2 alpha (AP-2 alpha), increased the expression of miR-124 expression, and downregulated prolyl-4-hydroxylase alpha 1 (P4H alpha 1) protein expression and collagen biosynthesis in cultured vascular smooth muscle cells. Importantly, these in vitro effects produced by high glucose were abolished by AMPK alpha pharmacological activation or adenovirus-mediated AMPK alpha overexpression. Further, adenovirus-mediated AMPK alpha gain of function remitted the process of diabetes-induced plaque destabilization in Apoe(-/-) mice injected with streptozotocin. Administration of metformin enhanced pAP-2 alpha level, reduced miR-124 expression, and increased P4H alpha 1 and collagens in carotid atherosclerotic plaque in diabetic Apoe(-/-) mice. We conclude that streptozotocin-induced toxic diabetes promotes the formation of unstable atherosclerotic plaques based on the vulnerability index in Apoe(-/-) mice, which is related to the inactivation of AMPK alpha/AP-2 alpha/miRNA-124/P4H alpha 1 axis. Clinically, targeting AMPK alpha/AP-2 alpha/miRNA-124/P4H alpha 1 signaling should be considered to increase the plaque stability in patients with atherosclerosis. Key messages Hyperglycemia reduced collagen synthesis, leading to the formation of unstable atherosclerotic plaque induced by collar placement around carotid in apolipoprotein E knockout mice. Hyperglycemia destabilizes atherosclerotic plaque in vivo through an AMPK alpha/AP-2 alpha/miRNA-124/P4H alpha 1-dependent collagen synthesis. Metformin functions as a stabilizer of atherosclerotic plaque to reduce acute coronary accent.