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

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Abstract

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 (AMPKα) and the transcriptional activity of activator protein 2 alpha (AP-2α), increased the expression of miR-124 expression, and downregulated prolyl-4-hydroxylase alpha 1 (P4Hα1) protein expression and collagen biosynthesis in cultured vascular smooth muscle cells. Importantly, these in vitro effects produced by high glucose were abolished by AMPKα pharmacological activation or adenovirus-mediated AMPKα overexpression. Further, adenovirus-mediated AMPKα gain of function remitted the process of diabetes-induced plaque destabilization in Apoe−/− mice injected with streptozotocin. Administration of metformin enhanced pAP-2α level, reduced miR-124 expression, and increased P4Hα1 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 AMPKα/AP-2α/miRNA-124/P4Hα1 axis. Clinically, targeting AMPKα/AP-2α/miRNA-124/P4Hα1 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 AMPKα/AP-2α/miRNA-124/P4Hα1-dependent collagen synthesis.

  • Metformin functions as a stabilizer of atherosclerotic plaque to reduce acute coronary accent.

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Acknowledgments

This work was supported by National Natural Science Foundation of China (81770493, 81320108004, 81370411, and 81470591).

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Authors and Affiliations

  1. The Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital, Shandong University School of Medicine, No. 107 West Culture Road, Jinan, Shandong, 250012, China

    Wen-Jing Liang, Sheng-Nan Zhou, Mei-Rong Shan, Xue-Qin Wang, Miao Zhang, Yuan Chen, Yun Zhang, Shuang-Xi Wang & Tao Guo

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  1. Wen-Jing Liang
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  7. Yun Zhang
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Contributions

W.J.L. designed and conducted the experiments and analyzed data. S.N.Z., M.R.S., X.Q.W., M.Z., Y.C., and X.Y.P. partially performed some experiments. Y.Z., T.G., and S.X.W. analyzed the data, wrote the manuscript, and convinced the whole project.

Corresponding authors

Correspondence to Yun Zhang, Shuang-Xi Wang or Tao Guo.

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Liang, WJ., Zhou, SN., Shan, MR. et al. AMPKα inactivation destabilizes atherosclerotic plaque in streptozotocin-induced diabetic mice through AP-2α/miRNA-124 axis. J Mol Med 96, 403–412 (2018). https://doi.org/10.1007/s00109-018-1627-8

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