Diabetes mellitus and its associated complications are a major health problem in the developed world. Diabetics are 2- to 4-times more likely to have cardiovascular diseases (CVD) than general population. One feature of diabetes that has become apparent in recent years is excess oxidant stress. In preliminary data presented here, we have found that hyperglycemia and free fatty acids (FFA), two hallmarks of type I and type II diabetes, impart an oxidant stress in endothelial cells. These results in lipid peroxidation, tyrosine nitration of prostacyclin synthase (PGIS), reduced NO bioactivity, endothelial nitric oxide synthase (eNOS) uncoupling, and insulin resistance. We have also found that treatment with the AMP-activated kinase (AMPK) activator, 5-amino-4-imidazole carboxamide riboside (AICAR), prevents all of these events including the increase in oxidant stress and insulin resistance from occurring. A basic premise of this proposal is that AMPK activation could protect the endothelial cell against the adverse effects of hyperglycemia and FFA by increasing mitochondrial uncoupling protein (UCP)-2 that lead to a decrease in oxidant stress in parallel with an increase in NO bioactivity. Therefore, as a central hypothesis of this application, we propose that vascular diathesis of insulin resistance and diabetes is due, in part, from a hyperglycemia/FFA-induced oxidant stress and a compensatory activation of AMPK. The next part of our proposal will determine the consequences of AMPK activation on oxidant stress, endothelial function, and insulin signaling, capitalizing on preliminary data that AICAR reduces both cellular oxidant stress and insulin resistance from glucose and fatty acids in vitro and aortic lesions in Apo-E knockout (KO) enhanced by diabetes in vivo. In order to accomplish this goal, we propose to study 1). To determine if activation of AMPK by a number of means (pharmacological and molecular biological means) reduces oxidant stress and insulin resistance and to evaluate how it works, and 2). To determine if AMPK-dependent reduction in oxidant stress and endothelial dysfunction is operating in diabetes in vivo. This powerful combination of in vitro and in vivo techniques will provide novel information as to how the metabolic stresses associated with diabetes cause damage to the endothelium. They should also yield insights into how endothelium attempts to protect itself against these stresses and whether AMPK is a potential target for therapy for diabetes.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL080499-01A1
Application #
7101374
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Rabadan-Diehl, Cristina
Project Start
2006-04-01
Project End
2011-03-31
Budget Start
2006-04-01
Budget End
2007-03-31
Support Year
1
Fiscal Year
2006
Total Cost
$366,250
Indirect Cost
Name
University of Oklahoma Health Sciences Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
878648294
City
Oklahoma City
State
OK
Country
United States
Zip Code
73117
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
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
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
Dai, Xiaoyan; Okon, Imoh; Zou, Ming-Hui (2017) Myeloid cell neuropilin 1 ameliorates high-fat diet-induced insulin resistance via suppression of Nlrp3 inflammasome. Macrophage (Houst) 4:
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

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