AMPKα inactivation destabilizes atherosclerotic plaque in streptozotocin-induced diabetic mice through AP-2α/miRNA-124 axis
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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.
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.
KeywordsAMPKα Diabetes Atherosclerosis AP-2α miR-124 P4Hα1
This work was supported by National Natural Science Foundation of China (81770493, 81320108004, 81370411, and 81470591).
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.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
- 12.Zang M, Xu S, Maitland-Toolan KA, Zuccollo A, Hou X, Jiang B, Wierzbicki M, Verbeuren TJ, Cohen RA (2006) Polyphenols stimulate AMP-activated protein kinase, lower lipids, and inhibit accelerated atherosclerosis in diabetic LDL receptor-deficient mice. Diabetes 55:2180–2191CrossRefPubMedGoogle Scholar
- 13.Li Y, Xu S, Mihaylova MM, Zheng B, Hou X, Jiang B, Park O, Luo Z, Lefai E, Shyy JY, Gao B, Wierzbicki M, Verbeuren TJ, Shaw RJ, Cohen RA, Zang M (2011) AMPK phosphorylates and inhibits SREBP activity to attenuate hepatic steatosis and atherosclerosis in diet-induced insulin-resistant mice. Cell Metab 13:376–388CrossRefPubMedPubMedCentralGoogle Scholar
- 14.Park MJ, Kwak HJ, Lee HC, Yoo DH, Park IC, Kim MS, Lee SH, Rhee CH, Hong SI (2007) Nerve growth factor induces endothelial cell invasion and cord formation by promoting matrix metalloproteinase-2 expression through the phosphatidylinositol 3-kinase/Akt signaling pathway and AP-2 transcription factor. J Biol Chem 282:30485–30496CrossRefPubMedGoogle Scholar
- 19.Li P, Yin YL, Guo T, Sun XY, Ma H, Zhu ML, Zhao FR, Xu P, Chen Y, Wan GR, Jiang F, Peng QS, Liu C, Liu LY, Wang SX (2016) Inhibition of aberrant microRNA-133a expression in endothelial cells by statin prevents endothelial dysfunction by targeting GTP cyclohydrolase 1 in vivo. Circulation 134:1752–1765CrossRefPubMedPubMedCentralGoogle Scholar
- 20.Nagareddy PR, Murphy AJ, Stirzaker RA, Hu Y, Yu S, Miller RG, Ramkhelawon B, Distel E, Westerterp M, Huang LS, Schmidt AM, Orchard TJ, Fisher EA, Tall AR, Goldberg IJ (2013) Hyperglycemia promotes myelopoiesis and impairs the resolution of atherosclerosis. Cell Metab 17:695–708CrossRefPubMedPubMedCentralGoogle Scholar
- 24.Wang F, Ma H, Liang WJ, Yang JJ, Wang XQ, Shan MR, Chen Y, Jia M, Yin YL, Sun XY, Zhang JN, Peng QS, Chen YG, Liu LY, Li P, Guo T, Wang SX (2017) Lovastatin upregulates microRNA-29b to reduce oxidative stress in rats with multiple cardiovascular risk factors. Oncotarget 8:9021–9034PubMedPubMedCentralGoogle Scholar
- 25.Chakravarthi BV, Pathi SS, Goswami MT, Cieslik M, Zheng H, Nallasivam S, Arekapudi SR, Jing X, Siddiqui J, Athanikar J, Carskadon SL, Lonigro RJ, Kunju LP, Chinnaiyan AM, Palanisamy N, Varambally S (2014) The miR-124-prolyl hydroxylase P4HA1-MMP1 axis plays a critical role in prostate cancer progression. Oncotarget 5:6654–6669CrossRefPubMedPubMedCentralGoogle Scholar
- 27.Sun H, Zhang X, Zhao L, Zhen X, Huang S, Wang S, He H, Liu Z, Xu N, Yang F, Qu Z, Ma Z, Zhang C, Zhang Y, Hu Q (2015) Attenuation of atherosclerotic lesions in diabetic apolipoprotein E-deficient mice using gene silencing of macrophage migration inhibitory factor. J Cell Mol Med 19:836–849CrossRefPubMedPubMedCentralGoogle Scholar
- 28.Iwamoto N, Abe-Dohmae S, Ayaori M, Tanaka N, Kusuhara M, Ohsuzu F, Yokoyama S (2007) ATP-binding cassette transporter A1 gene transcription is downregulated by activator protein 2alpha. Doxazosin inhibits activator protein 2alpha and increases high-density lipoprotein biogenesis independent of alpha1-adrenoceptor blockade. Circ Res 101:156–165CrossRefPubMedGoogle Scholar
- 31.Utsugi T, Yoon JW, Park BJ, Imamura M, Averill N, Kawazu S, Santamaria P (1996) Major histocompatibility complex class I-restricted infiltration and destruction of pancreatic islets by NOD mouse-derived beta-cell cytotoxic CD8+ T-cell clones in vivo. Diabetes 45:1121–1131CrossRefPubMedGoogle Scholar
- 32.Low Wang CC, Hess CN, Hiatt WR, Goldfine AB (2016) Clinical update: cardiovascular disease in diabetes mellitus: atherosclerotic cardiovascular disease and heart failure in type 2 diabetes mellitus—mechanisms, management, and clinical considerations. Circulation 133:2459–2502CrossRefPubMedPubMedCentralGoogle Scholar