Prevention of high fat diet-induced vascular injury

Summary

Principal Investigator: Ming Hui Zou
Abstract: DESCRIPTION (provided by applicant): Overwhelming data from epidemiological studies and clinical trials reveal that consumption of fish oils (omega-3 polyunsaturated fatty acids) reduces cardiovascular deaths (CVD) and retards the progression of atherosclerosis in patients with coronary heart diseases. However, the cellular and molecular mechanisms by which omega-3 polyunsaturated fatty acids exert their protective effects remain poorly understood. Exciting data from the applicant's laboratory has revealed that administration of omega-3 polyunsaturated fatty acids significantly increased the phosphorylation of AMPK at Thr172 and AMPK activity. Activation of AMPK suppresses 26S proteasomes, the activation of nuclear factor kappa B, and the expression of NAD(P)H oxidase. Consistently, genetic deletion of AMPK12 in either ApoE knockout (Apo E-/-) or LDL receptor knockout (LDLr-/-) strain markedly increased 26S proteasome activity, I?B degradation, NF:B transactivation, NAD(P)H oxidase subunit overexpression, oxidative stress, endothelial dysfunction, and atherosclerosis, all of which were largely suppressed by chronic administration of MG132, a potent and cell permeable proteasome inhibitor. The central hypothesis of the current application is that selective activation of AMPK by omega-3 polyunsaturated fatty acids inhibits 26S proteasomes and NF-?B-mediated overexpression of NAD(P)H oxidase resulting in decreased oxidative stress, a key factor in vascular injury caused by high fat diets (HFD). Comprehensive experimental approaches including pharmacological and genetic means (siRNA and adenoviruses) will be used (1) to establish the essential roles of AMPK activation in omega-3 polyunsaturated fatty acids-induced suppression of NF:B-mediated aberrant expression of NAD(P)H oxidase in endothelial cells;(2) to elucidate the central roles of AMPK and 26S proteasome in omega-3 polyunsaturated fatty acids-induced inhibition on NF:B- mediated overexpression of NAD(P)H oxidase in endothelial cells;(3) to dissect the molecular mechanisms by which AMPK suppresses 26S proteasome activity, and (4) to assess the effects of AMPK on endothelial function and atherosclerosis in mice with the endothelium-specific depletion of AMPK (Tg-Cre-AMPK 11 or 12 (flox/flox), loss-of function) or in mice with the endothelium-specific overexpression of a constitutively active AMPK (Tg-CAAMPK, gain-of-function) in vivo. This powerful combination of in vitro and in vivo techniques and gain-/loss-of-function approaches will yield important insights into how omega-3 polyunsaturated fatty acids protect against cardiovascular diseases. Importantly, completion of the proposed studies will also provide novel insights into whether 26S proteasomes and AMPK are potential therapeutic targets for countering atherosclerosis associated with common diseases including aging, obesity, diabetes, and hypertension. PUBLIC HEALTH RELEVANCE: Overwhelming data from epidemiological studies and clinical trials reveal that consumption of fish oils and omega-3 polyunsaturated fatty acids reduces cardiovascular deaths (CVD) and retards the progression of atherosclerosis in patients with coronary heart diseases. However, the cellular and molecular mechanisms by which fish oils (omega-3 polyunsaturated fatty acids) exert their protective effects remain poorly understood. In this application, comprehensive experimental approaches will be used to test the central hypothesis that selective activation of AMPK by EPA inhibits 26S proteasomes and NF-?B-mediated overexpression of NAD(P)H oxidase resulting in decreased oxidative stress, a key factor in vascular injury caused by high fat diets (HFD). It is anticipated that the completion of this project will yield important insights into how omega-3 polyunsaturated fatty acids protect against cardiovascular diseases.
Funding Period: 2010-07-15 - 2015-04-30
more information: NIH RePORT

Top Publications

  1. pmc Endothelial cell-specific liver kinase B1 deletion causes endothelial dysfunction and hypertension in mice in vivo
    Wencheng Zhang
    Section of Molecular Medicine, Department of Medicine W Z, Q W, Y W, C M, Z L, X D, Q W, M H Z and Department of Biochemistry and Molecular Biology Z L, M H Z, University of Oklahoma Health Sciences Center, Oklahoma City Department of Cardiology, First Affiliated Hospital of Xi an Jiaotong University Health Science Center, Xi an, China Y W, W L, Z Y Y, M H Z and Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Qilu Hospital of Shandong University, Jinan, Shandong, China M H Z
    Circulation 129:1428-39. 2014
  2. pmc Aberrant endoplasmic reticulum stress in vascular smooth muscle increases vascular contractility and blood pressure in mice deficient of AMP-activated protein kinase-α2 in vivo
    Bin Liang
    Section of Molecular Medicine, Department of Medicine, University of Oklahoma Health Science Center, Oklahoma City, OK 73104, USA
    Arterioscler Thromb Vasc Biol 33:595-604. 2013
  3. pmc Non-covalent interaction between polyubiquitin and GTP cyclohydrolase 1 dictates its degradation
    Yu Zhao
    Section of Molecular Medicine, Department of Medicine, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma, United States of America
    PLoS ONE 7:e43306. 2012
  4. pmc Activation of AMP-activated protein kinase alleviates high-glucose-induced dysfunction of brain microvascular endothelial cell tight-junction dynamics
    Chao Liu
    Hubei Province Key Laboratory on Cardiovascular, Cerebrovascular, and Metabolic Disorders, Xianning University, Xianning, Hubei 437100, China
    Free Radic Biol Med 53:1213-21. 2012
  5. pmc Regulation of the proteasome by AMPK in endothelial cells: the role of O-GlcNAc transferase (OGT)
    Jian Xu
    Division of Endocrinology, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America
    PLoS ONE 7:e36717. 2012
  6. pmc Activation of AMP-activated protein kinase α2 by nicotine instigates formation of abdominal aortic aneurysms in mice in vivo
    Shuangxi Wang
    Department of Medicine, Division of Molecular Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
    Nat Med 18:902-10. 2012
  7. pmc Activation of the AMP-activated protein kinase by eicosapentaenoic acid (EPA, 20:5 n-3) improves endothelial function in vivo
    Yong Wu
    Division of Endocrinology and Diabetes, Department of Medicine, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma, United States of America
    PLoS ONE 7:e35508. 2012
  8. pmc AMP-activated protein kinase, stress responses and cardiovascular diseases
    Shaobin Wang
    Section of Molecular Medicine, University of Oklahoma Health Science Center, Oklahoma City, OK 73104, USA
    Clin Sci (Lond) 122:555-73. 2012
  9. pmc Regulation of NAD(P)H oxidases by AMPK in cardiovascular systems
    Ping Song
    Section of Molecular Medicine, Department of Medicine, and Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
    Free Radic Biol Med 52:1607-19. 2012
  10. pmc Tyrosine nitration of PA700 links proteasome activation to endothelial dysfunction in mouse models with cardiovascular risk factors
    Jian Xu
    Division of Endocrinology and Diabetes, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America
    PLoS ONE 7:e29649. 2012

Research Grants

  1. Oxidant stress and diabetic endothelial dysfunction
    Ming Hui Zou; Fiscal Year: 2013
  2. LIPID AND LIPOPROTEIN METABOLISM IN ATHEROSCLEROSIS
    Alan M Fogelman; Fiscal Year: 2013
  3. The Center for Native and Pacific Health Disparities Research
    MARJORIE K LEIMOMI MALA MAU; Fiscal Year: 2013

Detail Information

Publications48

  1. pmc Endothelial cell-specific liver kinase B1 deletion causes endothelial dysfunction and hypertension in mice in vivo
    Wencheng Zhang
    Section of Molecular Medicine, Department of Medicine W Z, Q W, Y W, C M, Z L, X D, Q W, M H Z and Department of Biochemistry and Molecular Biology Z L, M H Z, University of Oklahoma Health Sciences Center, Oklahoma City Department of Cardiology, First Affiliated Hospital of Xi an Jiaotong University Health Science Center, Xi an, China Y W, W L, Z Y Y, M H Z and Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Qilu Hospital of Shandong University, Jinan, Shandong, China M H Z
    Circulation 129:1428-39. 2014
    ..Liver kinase B1 (LKB1), a tumor suppressor, is a central regulator of cell polarity and energy homeostasis. The role of LKB1 in endothelial function in vivo has not been explored...
  2. pmc Aberrant endoplasmic reticulum stress in vascular smooth muscle increases vascular contractility and blood pressure in mice deficient of AMP-activated protein kinase-α2 in vivo
    Bin Liang
    Section of Molecular Medicine, Department of Medicine, University of Oklahoma Health Science Center, Oklahoma City, OK 73104, USA
    Arterioscler Thromb Vasc Biol 33:595-604. 2013
    ..The aim of this study was to investigate whether aberrant ER stress causes abnormal vasoconstriction and consequent high blood pressure in mice...
  3. pmc Non-covalent interaction between polyubiquitin and GTP cyclohydrolase 1 dictates its degradation
    Yu Zhao
    Section of Molecular Medicine, Department of Medicine, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma, United States of America
    PLoS ONE 7:e43306. 2012
    ..Taken together, we conclude that GTPCH1 non-covalently interacts with polyubiquitin via an ubiquitin-binding domain. The polyubiquitin binding directs GTPCH1 ubiquitination and proteasome degradation...
  4. pmc Activation of AMP-activated protein kinase alleviates high-glucose-induced dysfunction of brain microvascular endothelial cell tight-junction dynamics
    Chao Liu
    Hubei Province Key Laboratory on Cardiovascular, Cerebrovascular, and Metabolic Disorders, Xianning University, Xianning, Hubei 437100, China
    Free Radic Biol Med 53:1213-21. 2012
    ....
  5. pmc Regulation of the proteasome by AMPK in endothelial cells: the role of O-GlcNAc transferase (OGT)
    Jian Xu
    Division of Endocrinology, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America
    PLoS ONE 7:e36717. 2012
    ..Taken together, we conclude that AMPK functions as a physiological suppressor of 26S proteasomes...
  6. pmc Activation of AMP-activated protein kinase α2 by nicotine instigates formation of abdominal aortic aneurysms in mice in vivo
    Shuangxi Wang
    Department of Medicine, Division of Molecular Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
    Nat Med 18:902-10. 2012
    ..We conclude that smoking (through nicotine) instigates AAA through AMPK-α2–mediated AP-2α–dependent MMP2 expression in VSMCs...
  7. pmc Activation of the AMP-activated protein kinase by eicosapentaenoic acid (EPA, 20:5 n-3) improves endothelial function in vivo
    Yong Wu
    Division of Endocrinology and Diabetes, Department of Medicine, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma, United States of America
    PLoS ONE 7:e35508. 2012
    ..EPA via upregulation of UCP-2 activates AMPKα1 resulting in increased eNOS phosphorylation and consequent improvement of endothelial function in vivo...
  8. pmc AMP-activated protein kinase, stress responses and cardiovascular diseases
    Shaobin Wang
    Section of Molecular Medicine, University of Oklahoma Health Science Center, Oklahoma City, OK 73104, USA
    Clin Sci (Lond) 122:555-73. 2012
    ....
  9. pmc Regulation of NAD(P)H oxidases by AMPK in cardiovascular systems
    Ping Song
    Section of Molecular Medicine, Department of Medicine, and Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
    Free Radic Biol Med 52:1607-19. 2012
    ..In this review, we summarize our current understanding of how AMPK functions as a physiological repressor of NAD(P)H oxidase...
  10. pmc Tyrosine nitration of PA700 links proteasome activation to endothelial dysfunction in mouse models with cardiovascular risk factors
    Jian Xu
    Division of Endocrinology and Diabetes, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America
    PLoS ONE 7:e29649. 2012
    ..Taken together, these results suggest that 26S proteasome activation by ONOO(-)-induced PA700/S10B tyrosine nitration is a common route for endothelial dysfunction seen in mouse models of hypertension, diabetes, and dyslipidemia...
  11. pmc Inhibition of AMP-activated protein kinase α (AMPKα) by doxorubicin accentuates genotoxic stress and cell death in mouse embryonic fibroblasts and cardiomyocytes: role of p53 and SIRT1
    Shaobin Wang
    Division of Molecular Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA
    J Biol Chem 287:8001-12. 2012
    ..Taken together, these data suggest that AMPK inhibition by doxorubicin causes p53 accumulation and SIRT1 dysfunction in MEFs and further suggest that pharmacological activation of AMPK might alleviate the side effects of doxorubicin...
  12. pmc Inhibition of AMP-activated protein kinase accentuates lipopolysaccharide-induced lung endothelial barrier dysfunction and lung injury in vivo
    Junjie Xing
    Section of Molecular Medicine, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA
    Am J Pathol 182:1021-30. 2013
    ..We conclude that AMPK activity supports normal endothelial barrier function and that LPS exposure inhibits AMPK, thereby contributing to endothelial barrier dysfunction and lung injury...
  13. pmc Regulation of interplay between autophagy and apoptosis in the diabetic heart: new role of AMPK
    Ming Hui Zou
    Section of Molecular Medicine, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
    Autophagy 9:624-5. 2013
    ....
  14. pmc Redox regulation of endothelial cell fate
    Ping Song
    Section of Molecular Medicine, Department of Internal Medicine, University of Oklahoma Health Sciences Center, 941 Stanton L Young Blvd, Oklahoma City, OK, 73104, USA
    Cell Mol Life Sci 71:3219-39. 2014
    ..Future studies will examine if the redox biology of ECs can be targeted in pathophysiological conditions. ..
  15. pmc AMPK: a cellular metabolic and redox sensor. A minireview
    Najeeb A Shirwany
    Section of Molecular Medicine, Department of Medicine, University of Oklahoma Health Science Center, 941 Stanton L Young Blvd, Oklahoma City, OK 73104, USA
    Front Biosci (Landmark Ed) 19:447-74. 2014
    ..By inhibiting the formation of reactive oxygen species in the endothelium, AMPK can optimize the redox balance in the vasculature. Here, we review the role of AMPK in the cell. ..
  16. pmc Liver kinase B1 expression promotes phosphatase activity and abrogation of receptor tyrosine kinase phosphorylation in human cancer cells
    Imoh S Okon
    From the Section of Molecular Medicine, and
    J Biol Chem 289:1639-48. 2014
    ..Our findings provide novel insight on how LKB1 loss of expression or function promotes aberrant RTK signaling and rapid growth of cancer cells. ..
  17. pmc Activation of NAD(P)H oxidase by tryptophan-derived 3-hydroxykynurenine accelerates endothelial apoptosis and dysfunction in vivo
    Qiongxin Wang
    From Division of Molecular Medicine, Department of Medicine, and Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK
    Circ Res 114:480-92. 2014
    ..The kynurenine (Kyn) pathway is the major route for tryptophan (Trp) metabolism in mammals. The Trp-Kyn pathway is reported to regulate several fundamental biological processes, including cell death...
  18. pmc Adenosine monophosphate-activated protein kinase-α2 deficiency promotes vascular smooth muscle cell migration via S-phase kinase-associated protein 2 upregulation and E-cadherin downregulation
    Ping Song
    From the Section of Molecular Medicine, Department of Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK P S, Y Z, K A C, X D, H X, M H Z College of Medicine, Hubei, Province Key Laboratory on Cardiovascular, Cerebrovascular, and Metabolic Disorders, Hubei University of Science and Technology, Xianning, Hubei, China Y Z College of Medicine, Yangzhou University, Yangzhou, Jiangsu, China H X Institut Cochin, Universite Paris Descartes, CNRS UMR 8104, Paris, France B V and INSERM, U1016, Paris, France B V
    Arterioscler Thromb Vasc Biol 33:2800-9. 2013
    ..Adenosine monophosphate-activated protein kinase (AMPK) has been shown to play a pivotal role in cellular proliferation and migration. However, the roles of AMPK in VSMC migration and its underlying molecular mechanisms remain elusive...
  19. pmc Peroxynitrite-dependent zinc release and inactivation of guanosine 5'-triphosphate cyclohydrolase 1 instigate its ubiquitination in diabetes
    Yu Zhao
    Section of Molecular Medicine, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
    Diabetes 62:4247-56. 2013
    ..Taken together, we conclude that ONOO(-) releases zinc and inhibits GTPCH1, resulting in its ubiquitination and degradation of the enzyme. ..
  20. pmc Transcription factor Krüppel-like factor 2 plays a vital role in endothelial colony forming cells differentiation
    Yimeng Song
    Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing 100191, China
    Cardiovasc Res 99:514-24. 2013
    ..However, the mechanisms underlying transcriptional regulation of ECFC differentiation still remain largely elusive. Here, we investigated the role of transcription factor Krüppel-like factor 2 (KLF2) in the regulation of ECFC function...
  21. pmc Phosphorylation of serine 399 in LKB1 protein short form by protein kinase Cζ is required for its nucleocytoplasmic transport and consequent AMP-activated protein kinase (AMPK) activation
    Huaiping Zhu
    Section of Molecular Medicine, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73013, USA
    J Biol Chem 288:16495-505. 2013
    ..We conclude that, similar to Ser-428/431 (in LKB1(L)), Ser-399 (in LKB1(S)) is a PKCζ-dependent phosphorylation site essential for nucleocytoplasmic export of LKB1(S) and consequent AMPK activation...
  22. pmc Liver kinase B1 is required for thromboxane receptor-dependent nuclear factor-κB activation and inflammatory responses
    Jinlong He
    Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, China
    Arterioscler Thromb Vasc Biol 33:1297-305. 2013
    ..The aims of the present study were to determine the contributions of NF-κB activation to TPr-triggered vascular inflammation and elucidate the mechanism(s) underlying TPr activation of NF-κB...
  23. pmc Liver kinase b1 is required for white adipose tissue growth and differentiation
    Wencheng Zhang
    Section of Molecule Medicine, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
    Diabetes 62:2347-58. 2013
    ..Taken together, these data indicate that LKB1 controls IRS1-dependent adipogenesis via AMPK in WAT. ..
  24. pmc Tyrosine nitration of prostacyclin synthase is associated with enhanced retinal cell apoptosis in diabetes
    Ming Hui Zou
    Section of Molecular Medicine, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA
    Am J Pathol 179:2835-44. 2011
    ..In conclusion, oxidized LDL-mediated PGIS nitration and associated thromboxane receptor stimulation might be important in the initiation and progression of diabetic retinopathy...
  25. pmc AMPKα2 deletion exacerbates neointima formation by upregulating Skp2 in vascular smooth muscle cells
    Ping Song
    Section of Molecular Medicine, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, 73104, USA
    Circ Res 109:1230-9. 2011
    ..Whether AMPKα alters vascular neointima formation induced by vascular injury is unknown...
  26. pmc Reduction of AMP-activated protein kinase alpha2 increases endoplasmic reticulum stress and atherosclerosis in vivo
    Yunzhou Dong
    Department of Medicine and Endocrinology, University of Oklahoma Health Science Center, Oklahoma City, OK 73104, USA
    Circulation 121:792-803. 2010
    ..The mechanism by which aberrant ER stress develops is poorly understood. This study investigated whether dysfunction of AMP-activated protein kinase (AMPK) causes aberrant ER stress and atherosclerosis in vivo...
  27. pmc Tyrosine nitration of PA700 activates the 26S proteasome to induce endothelial dysfunction in mice with angiotensin II-induced hypertension
    Jian Xu
    Division of Endocrinology and Diabetes, Department of Medicine, University of Oklahoma Health Sciences Center, 941 Stanton L Young Blvd, Oklahoma City, OK 73104, USA
    Hypertension 54:625-32. 2009
    ..We conclude that Ang II increases tyrosine nitration of PA700 resulting in accelerated GTP cyclohydrolase I degradation, BH4 deficiency, and consequent endothelial dysfunction in hypertension...
  28. pmc Acute inhibition of guanosine triphosphate cyclohydrolase 1 uncouples endothelial nitric oxide synthase and elevates blood pressure
    Shuangxi Wang
    Department of Medicine, Division of Endocrinology and Diabetes, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
    Hypertension 52:484-90. 2008
    ..In conclusion, GTPCH1 via BH4 maintains normal BP and endothelial function in vivo by preserving NO synthesis by eNOS...
  29. pmc Activation of protease calpain by oxidized and glycated LDL increases the degradation of endothelial nitric oxide synthase
    Yunzhou Dong
    Harold Hamm Oklahoma Diabetes Center, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
    J Cell Mol Med 13:2899-910. 2009
    ..HOG-LDL may impair endothelial function by inducing calpain-mediated eNOS degradation in a ROS- and Ca(2+)-dependent manner...
  30. pmc Pigment epithelium-derived factor mitigates inflammation and oxidative stress in retinal pericytes exposed to oxidized low-density lipoprotein
    Sarah X Zhang
    Department of Medicine Endocrinology, Harold Hamm Oklahoma Diabetes Center, University of Oklahoma Health Sciences Center, 941 Stanton L Young Boulevard, 331A, Oklahoma City, Oklahoma 73104, USA
    J Mol Endocrinol 41:135-43. 2008
    ..Suppressing MCP-1 production and thus inhibiting macrophage recruitment may represent a new mechanism for the salutary effect of PEDF in diabetic retinopathy and warrants more studies in future...
  31. pmc Reactive nitrogen species is required for the activation of the AMP-activated protein kinase by statin in vivo
    Hyoung Chul Choi
    Sections of Endocrinology and Nephrology, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
    J Biol Chem 283:20186-97. 2008
    ..Taken together, our data suggest that AMPK activation by statin is peroxynitrite-mediated but PKC-zeta-dependent...
  32. pmc Phosphorylation of LKB1 at serine 428 by protein kinase C-zeta is required for metformin-enhanced activation of the AMP-activated protein kinase in endothelial cells
    Zhonglin Xie
    Division of Endocrinology and Diabetes, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
    Circulation 117:952-62. 2008
    ..The objective of the present study was to determine how metformin activates AMPK in endothelial cells...
  33. pmc AMP-activated protein kinase activation as a strategy for protecting vascular endothelial function
    Ming Hui Zou
    Section of Endocrinology and Diabetes, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA
    Clin Exp Pharmacol Physiol 35:535-45. 2008
    ..We further hypothesize that AMPK is a dual sensor for energy and redox status within a cell and AMPK may be a therapeutic target for protecting vascular endothelial function...
  34. pmc Thromboxane receptor activates the AMP-activated protein kinase in vascular smooth muscle cells via hydrogen peroxide
    Miao Zhang
    Division of Endocrinology and Diabetes, Department of Medicine, University of Oklahoma Health Science Center, 941 Stanton L Young Blvd, Oklahoma City, OK 73104, USA
    Circ Res 102:328-37. 2008
    ..We conclude that TPr stimulation triggers reactive oxygen species-mediated LKB1-dependent AMPK activation, which in return inhibits cellular protein synthesis in VSMCs...
  35. pmc AMPKalpha2 deletion causes aberrant expression and activation of NAD(P)H oxidase and consequent endothelial dysfunction in vivo: role of 26S proteasomes
    Shuangxi Wang
    Section of Endocrinology and Diabetes, Department of Medicine, University of Oklahoma Health Science Center, Oklahoma City, OK 73104, USA
    Circ Res 106:1117-28. 2010
    ..Recent studies suggest that AMPK activation improves endothelial function by counteracting oxidative stress in endothelial cells. How AMPK suppresses oxidative stress remains to be established...
  36. pmc Activation of AMP-activated protein kinase alpha1 alleviates endothelial cell apoptosis by increasing the expression of anti-apoptotic proteins Bcl-2 and survivin
    Chao Liu
    Section of Endocrinology and Diabetes, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA
    J Biol Chem 285:15346-55. 2010
    ..Overall, our results suggest that AMPKalpha1, but not AMPKalpha2 activation, promotes cell survival by increasing NF-kappaB-mediated expression of anti-apoptotic proteins (Bcl-2 and Survivin) and intracellular ATP contents...
  37. pmc Impaired expression of uncoupling protein 2 causes defective postischemic angiogenesis in mice deficient in AMP-activated protein kinase α subunits
    Ming jiang Xu
    Section of Molecular Medicine, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, 73104, USA
    Arterioscler Thromb Vasc Biol 31:1757-65. 2011
    ..The aim of the present study was to determine whether mitochondrial uncoupling protein (UCP) 2 is required for AMPK-dependent angiogenesis in ischemia in vivo...
  38. pmc Improvement of cardiac functions by chronic metformin treatment is associated with enhanced cardiac autophagy in diabetic OVE26 mice
    Zhonglin Xie
    Section of Molecular Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
    Diabetes 60:1770-8. 2011
    ..We investigated whether chronic activation of the AMP-activated protein kinase (AMPK) by metformin restores cardiac function and cardiomyocyte autophagy in OVE26 diabetic mice...
  39. pmc Inhibition of the AMP-activated protein kinase-α2 accentuates agonist-induced vascular smooth muscle contraction and high blood pressure in mice
    Shuangxi Wang
    Division of Molecular Medicine, Department of Medicine, University of Oklahoma Health Sciences Center, BSEB 325, 941 Stanton L Young Blvd, Oklahoma City, OK 73104, USA
    Hypertension 57:1010-7. 2011
    ....
  40. pmc 2-Deoxy-D-glucose treatment of endothelial cells induces autophagy by reactive oxygen species-mediated activation of the AMP-activated protein kinase
    Qilong Wang
    Section of Molecular Medicine, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America
    PLoS ONE 6:e17234. 2011
    ..Thus, AMPK is required for ROS-triggered autophagy in endothelial cells, which increases endothelial cell survival in response to cell stress...
  41. pmc Redox regulation of the AMP-activated protein kinase
    Yingying Han
    Department of Biochemistry and Department of Medicine, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma, United States of America
    PLoS ONE 5:e15420. 2010
    ..Redox state is a critical determinant of cell function, and any major imbalances can cause severe damage or death...
  42. pmc Activation of NAD(P)H oxidases by thromboxane A2 receptor uncouples endothelial nitric oxide synthase
    Miao Zhang
    Department of Medicine, University of Oklahoma Health Science Center, Oklahoma City, OK 73104, USA
    Arterioscler Thromb Vasc Biol 31:125-32. 2011
    ..How TPr stimulation causes vascular injury remains poorly defined. This study was conducted to investigate the mechanism by which TPr stimulation leads to vascular injury...
  43. pmc Arterial stiffness: a brief review
    Najeeb A Shirwany
    Department of Medicine, University of Oklahoma Health Science Center, Oklahoma City, 73104, USA
    Acta Pharmacol Sin 31:1267-76. 2010
    ..A critical discussion of new techniques for assessing vascular stiffness is also presented...
  44. pmc AMPK in cardiovascular health and disease
    Najeeb A Shirwany
    Department of Biochemistry, University of Oklahoma Health Sciences Center, Oklahoma City, 73104, USA
    Acta Pharmacol Sin 31:1075-84. 2010
    ..Dysfunctional AMPK is thought to underlie several cardiovascular pathologies. Here we review this kinase from its structure and discovery to current knowledge of its adaptive and maladaptive role in the cardiovascular system...
  45. pmc Improvement of mechanical heart function by trimetazidine in db/db mice
    Yuan jing Li
    Department of Internal Medicine and the Institute of Hypertension, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan 430030, China
    Acta Pharmacol Sin 31:560-9. 2010
    ..To investigate the influence of trimetazidine, which is known to be an antioxidant and modulator of metabolism, on cardiac function and the development of diabetic cardiomyopathy in db/db mouse...
  46. pmc Mechanisms underlying recoupling of eNOS by HMG-CoA reductase inhibition in a rat model of streptozotocin-induced diabetes mellitus
    Philip Wenzel
    Second Medical Clinic, Department of Cardiology and Angiology, Johannes Gutenberg University, Langenbeckstrasse 1, 55131 Mainz, Germany
    Atherosclerosis 198:65-76. 2008
    ....

Research Grants30

  1. Oxidant stress and diabetic endothelial dysfunction
    Ming Hui Zou; Fiscal Year: 2013
    ..abstract_text> ..
  2. LIPID AND LIPOPROTEIN METABOLISM IN ATHEROSCLEROSIS
    Alan M Fogelman; Fiscal Year: 2013
    ..These six Projects will be supported by four cores and together will form a highly interactive and synergistic Program Project that is focused on lipid and lipoprotein metabolism in atherosclerosis. ..
  3. The Center for Native and Pacific Health Disparities Research
    MARJORIE K LEIMOMI MALA MAU; Fiscal Year: 2013
    ..5) To prepare and empower our diverse Native and Pacific People communities to take ownership of their own health and wellness. ..