Atherosclerotic plaque rupture is the cause of acute coronary syndromes and symptomatic carotid artery disease in 75% of cases with high mortality. Most studies in animal models have focused on investigation of early stage lesions, not advanced lesions which in humans contribute to late stage clinical events. As such, our understanding of mechanisms and factors that control stability of late stage lesions is relatively poor. In many vascular diseases such as post-angioplasty restenosis and atherosclerosis, contractile vascular smooth muscle cells (VSMCs) undergo phenotypic modulation to a synthetic phenotypic in which VSMC exhibit increased proliferation and migration and decreased differentiation. Whether or not VSMC phenotypes controls plaque stability hasn't been well studied and, further, the factors controlling VSMC phenotype switch remain unknown. Our published and preliminary data including in this proposal have demonstrated that AMP-activated protein kinase (AMPK) ?2 deficiency results in decreased expression of contractile proteins and increased synthetic proteins in the plaque and promotes the features of unstable plaques in vivo. Mechanistically, we have found that AMPK?2 deficiency upregulates the expression of Krppel-like factor 4 (KLF4), which is a key regulator of VSMC phenotypic switch. Based on this exciting preliminary data, we hypothesize that AMPK?2 is essential in suppressing atherosclerotic plaque growth and vulnerability by inhibiting the VSMC phenotypic switching in a KLF4-dependent mechanism. This hypothesis will be tested in three aims.
Aim 1 is to establish the essential role of AMPK?2 in regulating VSMC phenotypical switch, atherosclerosis, and the instability of atherosclerotic plaques in VSMC-specific ApoE-/- /AMPK?2-/- double knockout mice (Apoe?/?AMPK?2sm-/-) with or without metformin, a potent AMPK activator; After that, we will determine if phenotypic transitions observed in our mouse studies also occur in human atherosclerotic lesions (from autopsy samples).
Aim 2 is to demonstrate that KLF4 is required for AMPK?2-deficiency-induced VSMC phenotypic switching. We fully anticipate the completion of the proposed studies will provide the rationales for developing AMPK?2-specific agonists as novel strategies for the prevention and efficient treatment of plaque destabilization and rupture that contribute to end stage clinical events leading to myocardial infarction and stroke.

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The goal of this competitive renewal application is to establish the essential roles of AMP-activated protein kinase alpha 2 in VSMC phenotypes and atherosclerotic plaque stability. The completion of this project will provide the rationales for developing AMPK?2-specific agonists as novel strategies for the prevention and efficient treatment of plaque destabilization and rupture that contribute to end stage clinical events leading to myocardial infarction and stroke.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Schopfer, David Wesley
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Georgia State University
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Yu, Xi-Yong; Song, Ping; Zou, Ming-Hui (2018) Obesity Paradox and Smoking Gun: A Mystery of Statistical Confounding? Circ Res 122:1642-1644
Wang, Bei; Nie, Jiali; Wu, Lujin et al. (2018) AMPK?2 Protects Against the Development of Heart Failure by Enhancing Mitophagy via PINK1 Phosphorylation. Circ Res 122:712-729
Lu, Qiulun; Xie, Zhonglin; Yan, Chenghui et al. (2018) SNRK (Sucrose Nonfermenting 1-Related Kinase) Promotes Angiogenesis In Vivo. Arterioscler Thromb Vasc Biol 38:373-385
Han, Young-Min; Bedarida, Tatiana; Ding, Ye et al. (2018) ?-Hydroxybutyrate Prevents Vascular Senescence through hnRNP A1-Mediated Upregulation of Oct4. Mol Cell 71:1064-1078.e5
Wang, Qiongxin; Ding, Ye; Song, Ping et al. (2017) Tryptophan-Derived 3-Hydroxyanthranilic Acid Contributes to Angiotensin II-Induced Abdominal Aortic Aneurysm Formation in Mice In Vivo. Circulation 136:2271-2283
Duan, Quanlu; Song, Ping; Ding, Ye et al. (2017) Activation of AMP-activated protein kinase by metformin ablates angiotensin II-induced endoplasmic reticulum stress and hypertension in mice in vivo. Br J Pharmacol 174:2140-2151
Liu, Zhaoyu; Zhu, Huaiping; Dai, Xiaoyan et al. (2017) Macrophage Liver Kinase B1 Inhibits Foam Cell Formation and Atherosclerosis. Circ Res 121:1047-1057
Wang, Qilong; Zhang, Miao; Torres, Gloria et al. (2017) Metformin Suppresses Diabetes-Accelerated Atherosclerosis via the Inhibition of Drp1-Mediated Mitochondrial Fission. Diabetes 66:193-205
Okon, Imoh; Ding, Ye; Zou, Ming-Hui (2017) Ablation of Interferon Regulatory Factor 3 Promotes the Stability of Atherosclerotic Plaques. Hypertension 69:407-408
Dai, Xiaoyan; Okon, Imoh; Liu, Zhaoyu et al. (2017) Ablation of Neuropilin 1 in Myeloid Cells Exacerbates High-Fat Diet-Induced Insulin Resistance Through Nlrp3 Inflammasome In Vivo. Diabetes 66:2424-2435

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