Our published data and the preliminary data presented in this application have demonstrated that hyperglycemia suppresses AMPK, which in turn perpetuates oxidative stress and vascular injury in diabetes. The central hypothesis of this application is that AMPK12 inhibition increases 26S activity, which increases I:B1 degradation, p65 nucleus localization, and consequent NF:B activation. Activated NF:B binds to the promoter of NAD(P)H oxidase subunits, including NOX4, gp91phox(NOX2), p67phox, p47phox, resulting in an increase in NAD(P)H oxidase activity and ROS, which causes endothelial cell dysfunction and accelerated atherosclerosis. Chronic proteasome inhibition of the 26S proteasome prevents endothelial dysfunction and atherogenesis by inhibiting proteasome-dependent NF:B-mediated activation of NAD(P)H oxidase. This hypothesis will be tested in three interrelated aims. These first two aims are designed to establish whether chronic hyperglycemia inhibition AMPK functions (Aim #1) and whether AMPK inhibition causes abnormal expression of adhesion molecules and oxidant stress in diabetes (Aim #2). Finally, we will test the contributions of RNS-mediated AMPK inhibition in the development of accelerated atherosclerosis in diabetes (Aim #3). Although the in vivo relationships among atherosclerosis, oxidant stress, and AMPK in diabetes are undoubtedly complex, the emerging role for AMPK in oxidant stress and atherosclerosis warrant further study. The studies proposed here represent the first set of definitive studies to determine the role of ONOO- and AMPK inhibition in the pathogenesis of diabetic vascular dysfunction and atherosclerosis. As such, they have the potential to explain the long recognized decrease in AMPK that occurs in animals and human patients with diabetes. We believe that the proposed studies will provide novel information as to how the metabolic stress associated with diabetes causes damage to the endothelium and how the endothelial cell attempts to protect itself against these stresses and whether ONOO- or AMPK are potential targets for therapy.

Public Health Relevance

Recent studies from the applicant's group and others support the idea that oxidant stress is a common pathogenic mechanism for cardiovascular diseases including diabetes, hypertension, and atherosclerosis. But the mechanisms are poorly defined. Thus, this application is aimed to determine 1) how diabetes inhibits AMPK in endothelial cells;2) To determine how AMPK inhibition results in excessive inflammation and oxidant stress;and 3) to determine the contribution of AMPK inhibition in diabetes-enhanced atherosclerosis in mouse models of atherosclerosis in vivo.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Vascular Cell and Molecular Biology Study Section (VCMB)
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Liu, Lijuan
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University of Oklahoma Health Sciences Center
Internal Medicine/Medicine
Schools of Medicine
Oklahoma City
United States
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Song, Ping; Zou, Ming-Hui (2014) Redox regulation of endothelial cell fate. Cell Mol Life Sci 71:3219-39
Li, Hongliang; Min, Qing; Ouyang, Changhan et al. (2014) AMPK activation prevents excess nutrient-induced hepatic lipid accumulation by inhibiting mTORC1 signaling and endoplasmic reticulum stress response. Biochim Biophys Acta 1842:1844-54
Zhang, Wencheng; Wang, Qilong; Wu, Yue et al. (2014) Endothelial cell-specific liver kinase B1 deletion causes endothelial dysfunction and hypertension in mice in vivo. Circulation 129:1428-39
Okon, Imoh S; Coughlan, Kathleen A; Zou, Ming-Hui (2014) Liver kinase B1 expression promotes phosphatase activity and abrogation of receptor tyrosine kinase phosphorylation in human cancer cells. J Biol Chem 289:1639-48
Shirwany, Najeeb A; Zou, Ming-Hui (2014) AMPK: a cellular metabolic and redox sensor. A minireview. Front Biosci (Landmark Ed) 19:447-74
Li, Hongliang; Lee, Jiyeon; He, Chaoyong et al. (2014) Suppression of the mTORC1/STAT3/Notch1 pathway by activated AMPK prevents hepatic insulin resistance induced by excess amino acids. Am J Physiol Endocrinol Metab 306:E197-209
Zhu, Huaiping; Foretz, Marc; Xie, Zhonglin et al. (2014) PRKAA1/AMPK?1 is required for autophagy-dependent mitochondrial clearance during erythrocyte maturation. Autophagy 10:1522-34
Wang, Qiongxin; Zhang, Miao; Ding, Ye et al. (2014) Activation of NAD(P)H oxidase by tryptophan-derived 3-hydroxykynurenine accelerates endothelial apoptosis and dysfunction in vivo. Circ Res 114:480-92
Okon, Imoh S; Coughlan, Kathleen A; Zhang, Cheng et al. (2014) Protein kinase LKB1 promotes RAB7-mediated neuropilin-1 degradation to inhibit angiogenesis. J Clin Invest 124:4590-602
He, Jinlong; Zhou, Yanhong; Xing, Junjie et al. (2013) Liver kinase B1 is required for thromboxane receptor-dependent nuclear factor-*B activation and inflammatory responses. Arterioscler Thromb Vasc Biol 33:1297-305

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