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.
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.
|Zhang, Miao; Zhu, Huaiping; Ding, Ye et al. (2017) AMP-activated protein kinase ?1 promotes atherogenesis by increasing monocyte-to-macrophage differentiation. J Biol Chem 292:7888-7903|
|Wang, Bei; Nie, Jiali; Wu, Lujin et al. (2017) AMPK?2 Protects Against the Development of Heart Failure by Enhancing Mitophagy via PINK1 Phosphorylation. Circ Res :|
|Wu, Shengnan; Lu, Qiulun; Wang, Qilong et al. (2017) Binding of FUN14 Domain Containing 1 With Inositol 1,4,5-Trisphosphate Receptor in Mitochondria-Associated Endoplasmic Reticulum Membranes Maintains Mitochondrial Dynamics and Function in Hearts in Vivo. Circulation 136:2248-2266|
|Lu, Qiulun; Xie, Zhonglin; Yan, Chenghui et al. (2017) Snf1 (Sucrose Nonfermenting 1)-Related Kinase Promotes Angiogenesis In Vivo. Arterioscler Thromb Vasc Biol :|
|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|
|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|
|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|
|Song, Ping; Ramprasath, Tharmarajan; Wang, Huan et al. (2017) Abnormal kynurenine pathway of tryptophan catabolism in cardiovascular diseases. Cell Mol Life Sci 74:2899-2916|
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