PPAR-gamma and Vascular Lesion Formation

Summary

Principal Investigator: Yuqing Eugene Chen
Abstract: DESCRIPTION (provided by applicant): Emerging data suggest that peroxisome proliferator-activated receptor- ? (PPAR-?) is a critical determinant that may provide functional links between diabetes and CVD. During the past cycle of this R01 funding, our laboratory has made a series of significant contributions to better understand the role of PPAR-? activation in the vasculature. The insulin-sensitizing thiazolidinediones (TZDs) are synthetic ligands of PPAR-? and the first drugs used to treat insulin resistance in patients with type 2 diabetes. Despite of their effectiveness as insulin sensitizers and their protective effects in the vasculature, the therapeutic efficacy of TZDs has been severely compromised due to the appearance of associated cardiovascular events. Thus, the investigation of the molecular mechanisms underlying PPAR-? functions especially in the cardiovascular system are of utmost importance. Of significance, we have identified a nitric oxide (NO) and fatty acid-derived product, nitrated derivatives of fatty acids (NO2-FA) including nitrated oleic acid (OA- NO2) and linoleic acid (LNO2), as potent endogenous PPAR ? ligands. More recent analysis by our laboratories clearly documented that NO2-FA-activated PPAR ? recruits/displaces differential cofactors leading to a pattern of gene expression that mediate different biological responses compared to TZD-activated PPAR ?. Also, we have identified Kruppel-like factor 11 (KLF11) as a novel PPAR3 cofactor. Although KLF11 gene mutations cause MODY7, an early-onset type 2 diabetes mellitus, but its role in the vasculature is entirely unknown. Based on these key results, in this proposal we will test the central hypothesis that NO2-FA-modulated PPAR ? activation and the recruitment of KLF11 play a critical role in protecting the vasculature from vascular lesion formation, thereby contributing to maintenance of vascular homeostasis. Specifically, we will 1) Determine the molecular interactions between NO2-FA and PPAR-? in vascular remodeling;2) Define KLF11 as a novel PPAR-? cofactor required for PPAR-? function during vascular lesion formation. Advances in understanding the mechanisms of endogenous PPAR-? modulation will provide novel therapeutic strategies for treating diabetes and CVD. PUBLIC HEALTH RELEVANCE: Cardiovascular diseases (CVD) are the primary cause of mortality among diabetic patients accounting for almost 2 out of 3 deaths. The insulin-sensitizing thiazolidinediones (TZDs) are synthetic ligands of PPAR-? and the first drugs used to treat insulin resistance in patients with type 2 diabetes. Despite of their effectiveness as insulin sensitizers and their protective effects in the vasculature, the therapeutic efficacy of TZDs has been severely compromised due to the appearance of associated cardiovascular events. This proposal will explore mechanisms how the endogenous PPAR-? ligands, nitro-fatty acids modulate PPAR-? signaling to inhibit vascular lesion formation. The successful implementation of this proposal should lead to a better understanding of endogenous signaling actions of nitro-fatty acids in the vasculature and will provide novel approaches to develop the next generation of PPAR-? drugs with anti-diabetic and anti-CVD properties.
Funding Period: 2002-01-01 - 2015-11-30
more information: NIH RePORT

Top Publications

  1. pmc Perivascular adipose tissue in vascular function and disease: a review of current research and animal models
    Nicholas K Brown
    From the Department of Internal Medicine, Cardiovascular Center, University of Michigan Medical Center, Ann Arbor N K B, Z Z, J Z, D T E, Y E C, L C Center for Cancer and Immunology Research, Children s National Medical Center, Washington, DC N K B and Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, P R China R Z, J W
    Arterioscler Thromb Vasc Biol 34:1621-30. 2014
  2. pmc Biochemical characterization and cellular effects of CADASIL mutants of NOTCH3
    He Meng
    Department of Neurology, University of Michigan, Ann Arbor, Michigan, United States of America
    PLoS ONE 7:e44964. 2012
  3. pmc Loss of perivascular adipose tissue on peroxisome proliferator-activated receptor-γ deletion in smooth muscle cells impairs intravascular thermoregulation and enhances atherosclerosis
    Lin Chang
    Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI 48109, USA
    Circulation 126:1067-78. 2012
  4. pmc Construction of vascular tissues with macro-porous nano-fibrous scaffolds and smooth muscle cells enriched from differentiated embryonic stem cells
    Jiang Hu
    Department of Biologic and Materials Sciences, University of Michigan, Ann Arbor, Michigan, United States of America
    PLoS ONE 7:e35580. 2012
  5. pmc Yap1 protein regulates vascular smooth muscle cell phenotypic switch by interaction with myocardin
    Changqing Xie
    Cardiovascular Center, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA
    J Biol Chem 287:14598-605. 2012
  6. pmc Endothelial lipase mediates HDL levels in normal and hyperlipidemic rabbits
    Jifeng Zhang
    Department of Molecular Pathology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo City, Japan
    J Atheroscler Thromb 19:213-26. 2012
  7. ncbi MicroRNA and vascular smooth muscle cells
    Changqing Xie
    Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan, USA
    Vitam Horm 87:321-39. 2011
  8. pmc Identification and mechanism of 10-carbon fatty acid as modulating ligand of peroxisome proliferator-activated receptors
    Raghu R V Malapaka
    Laboratory of Structural Sciences, Van Andel Research Institute, Grand Rapids, MI 49503, USA
    J Biol Chem 287:183-95. 2012
  9. pmc Inhibition of gluconeogenic genes by calcium-regulated heat-stable protein 1 via repression of peroxisome proliferator-activated receptor α
    Yanbo Fan
    Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan 48109, USA
    J Biol Chem 286:40584-94. 2011
  10. pmc Monocyte chemotactic protein-induced protein 1 (MCPIP1) suppresses stress granule formation and determines apoptosis under stress
    Dongfei Qi
    Shock Trauma Research Center and Department of Basic Medical Science, School of Medicine, University of Missouri Kansas City, Kansas City, Missouri 64108, USA
    J Biol Chem 286:41692-700. 2011

Detail Information

Publications52

  1. pmc Perivascular adipose tissue in vascular function and disease: a review of current research and animal models
    Nicholas K Brown
    From the Department of Internal Medicine, Cardiovascular Center, University of Michigan Medical Center, Ann Arbor N K B, Z Z, J Z, D T E, Y E C, L C Center for Cancer and Immunology Research, Children s National Medical Center, Washington, DC N K B and Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, P R China R Z, J W
    Arterioscler Thromb Vasc Biol 34:1621-30. 2014
    ..We here discuss the accumulated knowledge of PVAT biology and related research on models of hypertension and atherosclerosis. ..
  2. pmc Biochemical characterization and cellular effects of CADASIL mutants of NOTCH3
    He Meng
    Department of Neurology, University of Michigan, Ann Arbor, Michigan, United States of America
    PLoS ONE 7:e44964. 2012
    ..We conclude that CADASIL mutants of NOTCH3 complex with NOTCH1, 3, and 4, slow NOTCH3 clearance, and that overexpressed wild type and mutant NOTCH3 protein interfere with key NOTCH-mediated functions in smooth muscle cells...
  3. pmc Loss of perivascular adipose tissue on peroxisome proliferator-activated receptor-γ deletion in smooth muscle cells impairs intravascular thermoregulation and enhances atherosclerosis
    Lin Chang
    Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI 48109, USA
    Circulation 126:1067-78. 2012
    ..We hypothesize that the thermogenic function of PVAT regulates intravascular temperature and reduces atherosclerosis...
  4. pmc Construction of vascular tissues with macro-porous nano-fibrous scaffolds and smooth muscle cells enriched from differentiated embryonic stem cells
    Jiang Hu
    Department of Biologic and Materials Sciences, University of Michigan, Ann Arbor, Michigan, United States of America
    PLoS ONE 7:e35580. 2012
    ..In conclusion, our results demonstrated the potential of SMCs derived from ESCs as a promising cell source for therapeutic vascular tissue engineering and disease model applications...
  5. pmc Yap1 protein regulates vascular smooth muscle cell phenotypic switch by interaction with myocardin
    Changqing Xie
    Cardiovascular Center, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA
    J Biol Chem 287:14598-605. 2012
    ....
  6. pmc Endothelial lipase mediates HDL levels in normal and hyperlipidemic rabbits
    Jifeng Zhang
    Department of Molecular Pathology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo City, Japan
    J Atheroscler Thromb 19:213-26. 2012
    ....
  7. ncbi MicroRNA and vascular smooth muscle cells
    Changqing Xie
    Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan, USA
    Vitam Horm 87:321-39. 2011
    ..Here, we review recent advances regarding functions of specific miRNAs in vasculature and discuss possible mechanisms by which miRNAs affect VSMC biology...
  8. pmc Identification and mechanism of 10-carbon fatty acid as modulating ligand of peroxisome proliferator-activated receptors
    Raghu R V Malapaka
    Laboratory of Structural Sciences, Van Andel Research Institute, Grand Rapids, MI 49503, USA
    J Biol Chem 287:183-95. 2012
    ..Together, these results suggest that DA is a modulating ligand for PPARs, and the structure can aid in designing better and safer PPARγ-based drugs...
  9. pmc Inhibition of gluconeogenic genes by calcium-regulated heat-stable protein 1 via repression of peroxisome proliferator-activated receptor α
    Yanbo Fan
    Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan 48109, USA
    J Biol Chem 286:40584-94. 2011
    ..Our data suggest that CARHSP1 inhibits hepatic gluconeogenic gene expression via repression of PPARα and that CARHSP1 may be a molecular target for the treatment of diabetes...
  10. pmc Monocyte chemotactic protein-induced protein 1 (MCPIP1) suppresses stress granule formation and determines apoptosis under stress
    Dongfei Qi
    Shock Trauma Research Center and Department of Basic Medical Science, School of Medicine, University of Missouri Kansas City, Kansas City, Missouri 64108, USA
    J Biol Chem 286:41692-700. 2011
    ..Taken together, these results suggest that MCPIP1 coordinates SG formation and apoptosis during cellular stress and may play a critical role in immune homeostasis and resolution of macrophage inflammation...
  11. pmc Three-dimensional growth of iPS cell-derived smooth muscle cells on nanofibrous scaffolds
    Changqing Xie
    Cardiovascular Center, Department of Internal Medicine, University of Michigan, Ann Arbor, 48109, USA
    Biomaterials 32:4369-75. 2011
    ..Upon subcutaneous implantation, the implanted cells maintained the SMC phenotype. In conclusion, the data suggest that iPSCs-derived SMCs can be an important cell source for personalized vascular tissue engineering applications...
  12. pmc Krüppel-like factor-11, a transcription factor involved in diabetes mellitus, suppresses endothelial cell activation via the nuclear factor-κB signaling pathway
    Yanbo Fan
    Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI 48109, USA
    Arterioscler Thromb Vasc Biol 32:2981-8. 2012
    ..However, the function of KLF11 in the cardiovascular system still remains to be uncovered. In this study, we aimed to investigate the role of KLF11 in vascular endothelial inflammation...
  13. pmc Novel keto-phospholipids are generated by monocytes and macrophages, detected in cystic fibrosis, and activate peroxisome proliferator-activated receptor-γ
    Victoria J Hammond
    School of Medicine, Cardiff University, Heath Park Campus, Cardiff CF14 4XN, United Kingdom
    J Biol Chem 287:41651-66. 2012
    ..The lipids are a new family of bioactive mediators from the 12/15-LOX pathway that may contribute to its known anti-inflammatory actions in vivo...
  14. pmc A tripeptide Diapin effectively lowers blood glucose levels in male type 2 diabetes mice by increasing blood levels of insulin and GLP-1
    Jifeng Zhang
    Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan, United States of America
    PLoS ONE 8:e83509. 2013
    ....
  15. pmc MCPIP1 deficiency in mice results in severe anemia related to autoimmune mechanisms
    Zhou Zhou
    Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan, United States of America
    PLoS ONE 8:e82542. 2013
    ..Thus, MCPIP1(-/-) mice may be a good mouse model for investigating the pathogenesis of pernicious anemia and testing the efficacy of some potential drugs for treatment of this disease...
  16. pmc Targeted disruption of MCPIP1/Zc3h12a results in fatal inflammatory disease
    Ruidong Miao
    Department of Basic Medical Science, School of Medicine, University of Missouri Kansas City, Kansas City, MO, USA
    Immunol Cell Biol 91:368-76. 2013
    ..Taken together, these results suggest a prominent role for MCPIP1 in the control of inflammation and immune homeostasis...
  17. pmc Dietary obesity-induced Egr-1 in adipocytes facilitates energy storage via suppression of FOXC2
    Jifeng Zhang
    Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, MSRB III 7301E, 1150 W Medical Center Drive, Ann Arbor, MI 48109, USA
    Sci Rep 3:1476. 2013
    ..Altogether, these studies suggest an important role for Egr-1, which, by repressing FOXC2 expression, promotes energy storage in WAT and favored the development of obesity under high energy intake...
  18. pmc MCPIP1 negatively regulates toll-like receptor 4 signaling and protects mice from LPS-induced septic shock
    Shengping Huang
    Department of Basic Medical Science, School of Medicine, University of Missouri Kansas City, Kansas City, MO 64108, USA
    Cell Signal 25:1228-34. 2013
    ..Taken together, these results suggest that MCPIP1 selectively suppresses TLR4 signaling pathway and protects mice from LPS-induced septic shock...
  19. pmc Zc3h12c inhibits vascular inflammation by repressing NF-κB activation and pro-inflammatory gene expression in endothelial cells
    Ling Liu
    Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI 48109, USA
    Biochem J 451:55-60. 2013
    ..Thus Zc3h12c is an endogenous inhibitor of TNFα-induced inflammatory signalling in HUVECs and might be a therapeutic target in vascular inflammatory diseases...
  20. pmc Electrophilic nitro-fatty acids inhibit vascular inflammation by disrupting LPS-dependent TLR4 signalling in lipid rafts
    Luis Villacorta
    Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, North Campus Research Complex Building 26 Room 355S, 2800 Plymouth Road, Ann Arbor, MI, USA
    Cardiovasc Res 98:116-24. 2013
    ....
  21. pmc Peroxisome proliferator-activated receptor γ coactivator 1β (PGC-1β) protein attenuates vascular lesion formation by inhibition of chromatin loading of minichromosome maintenance complex in smooth muscle cells
    Yanhong Guo
    Cardiovascular Center, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA
    J Biol Chem 288:4625-36. 2013
    ....
  22. pmc Human apolipoprotein A-II protects against diet-induced atherosclerosis in transgenic rabbits
    Yao Wang
    Department of Molecular Pathology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Shimokato, Chuo City, Yamanashi, Japan
    Arterioscler Thromb Vasc Biol 33:224-31. 2013
    ..We aimed to examine whether apo A-II plays any role in atherogenesis and, if so, to elucidate the mechanism involved...
  23. pmc Vascular PPARδ protects against stroke-induced brain injury
    Ke Jie Yin
    Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI 48109, USA
    Arterioscler Thromb Vasc Biol 31:574-81. 2011
    ..To investigate the effects of peroxisome proliferator-activated receptor (PPAR)δ in the cerebral vasculature following stroke-induced brain injury...
  24. pmc Vascular smooth muscle cell peroxisome proliferator-activated receptor-γ mediates pioglitazone-reduced vascular lesion formation
    Milton Hamblin
    Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, 1150 W Medical Center Drive, Ann Arbor, MI 48109, USA
    Arterioscler Thromb Vasc Biol 31:352-9. 2011
    ..In this study, we investigated the role of VSMC PPARγ-mediated signaling in transplantation-associated vascular lesion formation...
  25. pmc Expression profiling of nuclear receptors in human and mouse embryonic stem cells
    Chang Qing Xie
    Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI 48109, USA
    Mol Endocrinol 23:724-33. 2009
    ..These data should provide a unique resource for further exploration of the species-specific roles of NRs in ESC self-renewal and differentiation...
  26. pmc PPARgamma and its ligands: therapeutic implications in cardiovascular disease
    Luis Villacorta
    Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI 48109, USA
    Clin Sci (Lond) 116:205-18. 2009
    ..A new generation of insulin sensitizers with PPARgamma function for the treatment of diabetes may serve to limit patients from the increased cardiovascular burden of this disease...
  27. pmc PPARs and the cardiovascular system
    Milton Hamblin
    Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan 48109, USA
    Antioxid Redox Signal 11:1415-52. 2009
    ..Therefore, a better understanding of PPAR-dependent and -independent signaling will provide the foundation for future research on the role of PPARs in human cardiovascular biology...
  28. pmc A comparison of murine smooth muscle cells generated from embryonic versus induced pluripotent stem cells
    Chang Qing Xie
    Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI 48109, USA
    Stem Cells Dev 18:741-8. 2009
    ..Taken together, our data have established a simple iPS-SMC system to generate SMCs in vitro, which has tremendous potential to generate individualized SMCs for vascular tissue engineering and personalized drug screening...
  29. pmc Molecular recognition of nitrated fatty acids by PPAR gamma
    Yong Li
    Department of Pharmaceutical Sciences, Center for Pharmacogenetics, 709 Salk Hall, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA
    Nat Struct Mol Biol 15:865-7. 2008
    ..Structural and functional studies of receptor-ligand interactions reveal the molecular basis of PPAR gamma discrimination of various naturally occurring fatty acid derivatives...
  30. pmc Nitroalkenes suppress lipopolysaccharide-induced signal transducer and activator of transcription signaling in macrophages: a critical role of mitogen-activated protein kinase phosphatase 1
    Tomonaga Ichikawa
    Cardiovascular Medicine, University of Michigan Medical Center, Ann Arbor, Michigan 48109, USA
    Endocrinology 149:4086-94. 2008
    ..Taken together, our data demonstrate that nitroalkenes inhibit proinflammatory STAT signaling through inducting MKP-1 in macrophages...
  31. pmc Rad GTPase deficiency leads to cardiac hypertrophy
    Lin Chang
    Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI 48109, USA
    Circulation 116:2976-83. 2007
    ..Rad (Ras associated with diabetes) GTPase is the prototypic member of a subfamily of Ras-related small G proteins. The aim of the present study was to define whether Rad plays an important role in mediating cardiac hypertrophy...
  32. ncbi Cardiac peroxisome proliferator-activated receptor gamma is essential in protecting cardiomyocytes from oxidative damage
    Guoliang Ding
    Cardiovascular Research Institute, Morehouse School of Medicine, 720 Westview Dr SW, Atlanta, GA 30310, USA
    Cardiovasc Res 76:269-79. 2007
    ..However, little is known about the roles of PPARgamma in the heart. The present study is to investigate in vivo role(s) of PPARgamma in the heart...
  33. pmc Interleukin-1 beta-induced Id2 gene expression is mediated by Egr-1 in vascular smooth muscle cells
    Xiaojun Zhu
    Institute of Molecular Medicine, Peking University, No 5 Yi He Yuan Road, Beijing, 100871, PR China
    Cardiovasc Res 76:141-8. 2007
    ..However, the transcriptional regulation of Id2 gene expression in VSMC remains unexplored...
  34. pmc Nitro-linoleic acid inhibits vascular smooth muscle cell proliferation via the Keap1/Nrf2 signaling pathway
    Luis Villacorta
    Department of Internal Medicine, Cardiovascular Center, University of Michigan Medical Center, 1150 W Medical Center Drive, Ann Arbor, MI 48109, USA
    Am J Physiol Heart Circ Physiol 293:H770-6. 2007
    ..These studies provide the first evidence that nitroalkene LNO(2) inhibits VSMC proliferation through activation of the Keap1/Nrf2 signaling pathway, suggesting an important role of nitroalkenes in vascular biology...
  35. ncbi Transplantation of human undifferentiated embryonic stem cells into a myocardial infarction rat model
    Chang Qing Xie
    Cardiovascular Research Institute, Morehouse School of Medicine, Atlanta, GA 30310, USA
    Stem Cells Dev 16:25-9. 2007
    ....
  36. pmc Ligand-activated peroxisome proliferator-activated receptor-gamma protects against ischemic cerebral infarction and neuronal apoptosis by 14-3-3 epsilon upregulation
    Jui Sheng Wu
    Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
    Circulation 119:1124-34. 2009
    ..Their protective actions are considered to be peroxisome proliferator-activated receptor-gamma (PPAR-gamma)-dependent; however, it is unclear how PPAR-gamma activation confers resistance to ischemia-reperfusion injury...
  37. pmc Vascular smooth muscle cell-selective peroxisome proliferator-activated receptor-gamma deletion leads to hypotension
    Lin Chang
    Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI 48105, USA
    Circulation 119:2161-9. 2009
    ..Little evidence is available on the molecular mechanisms underlying the role of vascular smooth muscle cell-specific PPARgamma in basal vascular tone...
  38. pmc MicroRNA-1 regulates smooth muscle cell differentiation by repressing Kruppel-like factor 4
    Changqing Xie
    Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan 48109, USA
    Stem Cells Dev 20:205-10. 2011
    ..We conclude that miR-1 plays a critical role in the determination of SMC fate during retinoid acid-induced ESC/SMC differentiation, which may indicate that miR-1 has a role to promote SMC differentiation...
  39. pmc Porous nanofibrous PLLA scaffolds for vascular tissue engineering
    Jiang Hu
    Department of Biologic and Materials Sciences, University of Michigan, Ann Arbor, MI 48109 1078, USA
    Biomaterials 31:7971-7. 2010
    ..In vivo subcutaneous implantation studies confirmed HASMCs differentiation in the implants. Taken together, the results showed promising application of the porous NF PLLA scaffolds for reconstruction of tissue-engineered vascular grafts...
  40. pmc Vascular smooth muscle cell peroxisome proliferator-activated receptor-γ deletion promotes abdominal aortic aneurysms
    Milton Hamblin
    Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Mich, USA
    J Vasc Surg 52:984-93. 2010
    ..We hypothesized that PPARγ in smooth muscle cells (SMCs) attenuates the development of AAA. We also investigated PPARγ-mediated signaling pathways that may prevent the development of AAA...
  41. pmc Nitro-oleic acid inhibits angiotensin II-induced hypertension
    Jifeng Zhang
    Cardiovascular Center, College of Engineering, University of Michigan, USA
    Circ Res 107:540-8. 2010
    ..OA-NO(2) exerts cell signaling actions as a result of its strong electrophilic nature and mediates pleiotropic cell responses in the vasculature...
  42. pmc Involvement of inducible 6-phosphofructo-2-kinase in the anti-diabetic effect of peroxisome proliferator-activated receptor gamma activation in mice
    Xin Guo
    Intercollegiate Faculty of Nutrition, Department of Nutrition and Food Science, Texas A and M University, College Station, TX 77843, USA
    J Biol Chem 285:23711-20. 2010
    ..Together, these data demonstrate that PFKFB3/iPFK2 is critically involved in the anti-diabetic effect of PPARgamma activation...
  43. pmc Peroxisome proliferator-activated receptor delta regulation of miR-15a in ischemia-induced cerebral vascular endothelial injury
    Ke Jie Yin
    Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, University of Michigan, Ann Arbor, Michigan 48109, USA
    J Neurosci 30:6398-408. 2010
    ..Thus, regulation of PPARdelta-mediated miR-15a inhibition of bcl-2 could provide a novel therapeutic strategy for the treatment of stroke-related vascular dysfunction...
  44. pmc miR-10a contributes to retinoid acid-induced smooth muscle cell differentiation
    Huarong Huang
    Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan 48109, USA
    J Biol Chem 285:9383-9. 2010
    ..These studies suggest that miR-10a may play important roles in vascular biology and have implications for the diagnosis and treatment of vascular diseases...
  45. pmc Covalent peroxisome proliferator-activated receptor gamma adduction by nitro-fatty acids: selective ligand activity and anti-diabetic signaling actions
    Francisco J Schopfer
    Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA
    J Biol Chem 285:12321-33. 2010
    ..Administration of this class of signaling mediators to ob/ob mice revealed that NO(2)-FA lower insulin and glucose levels without inducing adverse side effects such as the increased weight gain induced by TZDs...
  46. pmc miR-497 regulates neuronal death in mouse brain after transient focal cerebral ischemia
    Ke Jie Yin
    Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI 48109, USA
    Neurobiol Dis 38:17-26. 2010
    ..We raise the possibility that this pathway may contribute to the pathogenesis of the ischemic brain injury in stroke...
  47. pmc Human C-reactive protein does not promote atherosclerosis in transgenic rabbits
    Tomonari Koike
    Department of Molecular Pathology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, 1110 Shimokato, Chuo City, Yamanashi, 409 3898, Japan
    Circulation 120:2088-94. 2009
    ....
  48. ncbi The role of peroxisome proliferator-activated receptor gamma in blood pressure regulation
    Milton Hamblin
    Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI 48109, USA
    Curr Hypertens Rep 11:239-45. 2009
    ..However, there is a need for further research regarding PPARgamma--mediated mechanisms involved in maintaining physiologic control of blood pressure...
  49. pmc Nitrated fatty acids: Endogenous anti-inflammatory signaling mediators
    Taixing Cui
    Cardiovascular Center, University of Michigan Medical Center, Ann Arbor, Michigan 48109, USA
    J Biol Chem 281:35686-98. 2006
    ..These observations indicate that nitroalkenes such as LNO2 and OA-NO2, derived from reactions of unsaturated fatty acids and oxides of nitrogen, are a class of endogenous anti-inflammatory mediators...