Skip to main content
SpringerLink
Log in

The Ubiquitin Proteasome System in Endothelial Cell Dysfunction and Vascular Disease

  • Chapter
  • First Online:
Molecular and Translational Vascular Medicine

Part of the book series: Molecular and Translational Medicine ((MOLEMED))

  • 816 Accesses

Abstract

Protein homeostasis is a critical cellular process to maintain protein function. Because the genome encodes for a very large number of discrete proteins and only a fraction of this number are needed or utilized for cellular function at a given time, a closely regulated system is necessary to control the synthesis, transport, and degradation of these molecules. The turnover of proteins can vary and cells tend to accumulate a large amount of expended, sometimes aberrantly folded and oxidized proteins that must be eliminated, degraded, and/or recycled. The majority of eukaryotic protein degradation is executed by the ubiquitin proteasome system (UPS). This system has acquired a central position in our understanding of cellular protein homeostasis. The UPS is one of the many posttranslational modifications of proteins that include acylation, alkylation, glycosylation, hydroxylation, and nitrosylation. These posttranslational modifications, while essential for protein homeostasis, if perturbed sufficiently, can also lead to pathological change. Abnormalities of the UPS have been implicated in the pathogenesis of a variety of diseases including cardiovascular disease. Accumulating evidence in recent years has strongly implicated the UPS in cardiovascular physiology and pathology. This chapter will review the role of the UPS in cardiovascular pathophysiology. We will describe the basic mechanistic underpinnings of the UPS and delineate its role in vascular physiology. The potential waypoints in the UPS signaling system where pathological events are known or thought to occur will be defined. Finally, an overview of how the UPS can be pharmacologically manipulated and whether this strategy has therapeutic currency will be presented.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 249.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Collins FS, Lander ES, Rogers J, Waterson RH. Finishing the euchromatic sequence of the human genome. Nature. 2004;431(7011):931–45.

    Google Scholar 

  2. Sorokin AV, Kim ER, Ovchinnikov LP. Proteasome system of protein degradation and processing. Biochemistry (Mosc). 2009;74(13):1411–42.

    Article  CAS  Google Scholar 

  3. Willis MS, Townley-Tilson WHD, Kang EY. Sent to destroy: the ubiquitin proteasome system regulates cell signaling and protein quality control in cardiovascular development and disease. Circ Res. 2010;106(3):463–78.

    Article  PubMed  CAS  Google Scholar 

  4. Stangl KL, Stangl V. The ubiquitin-proteasome pathway and endothelial (dys)function. Cardiovasc Res. 2010;85(2):281–90.

    Article  PubMed  CAS  Google Scholar 

  5. Kloetzel PM. Generation of major histocompatibility complex class I antigens: functional interplay between proteasomes and TPPII. Nat Immunol. 2004;5(7):661–9.

    Article  PubMed  CAS  Google Scholar 

  6. Glickman MH, Ciechanover A. The ubiquitin-proteasome proteolytic pathway: destruction for the sake of construction. Physiol Rev. 2002;82(2):373–428.

    PubMed  CAS  Google Scholar 

  7. Dantuma NP, Lindsten K. Stressing the ubiquitin-proteasome system. Cardiovasc Res. 2010;85(2):263–71.

    Article  PubMed  CAS  Google Scholar 

  8. Allende-Vega N, Saville MK. Targeting the ubiquitin-proteasome system to activate wild-type p53 for cancer therapy. Semin Cancer Biol. 2010;20(1):29–39.

    Article  PubMed  CAS  Google Scholar 

  9. Fang P, Lev-Lehman E, Tsai TF. The spectrum of mutations in UBE3A causing Angelman syndrome. Hum Mol Genet. 1999;8(1):129–35.

    Article  PubMed  CAS  Google Scholar 

  10. Ciechanover A, Orian A, Schwartz AL. Ubiquitin-mediated proteolysis: biological regulation via destruction. Bioessays. 2000;22(5):442–51.

    Article  PubMed  CAS  Google Scholar 

  11. Ciechanover A, Orian A, Schwartz AL. The ubiquitin-mediated proteolytic pathway: mode of action and clinical implications. J Cell Biochem Suppl. 2000;34:40–51.

    Article  PubMed  CAS  Google Scholar 

  12. Kornitzer D, Ciechanover A. Modes of regulation of ubiquitin-mediated protein degradation. J Cell Physiol. 2000;182(1):1–11.

    Article  PubMed  CAS  Google Scholar 

  13. Nie J, Wu Q, Liu W. Ectopic expression of ligand-of-numb protein X promoted TGF-beta induced epithelial to mesenchymal transition of proximal tubular epithelial cells. Biochim Biophys Acta. 2009;1792(2):122–31.

    Article  PubMed  CAS  Google Scholar 

  14. Nie J, McGill MA, Dermer M. LNX functions as a RING type E3 ubiquitin ligase that targets the cell fate determinant Numb for ubiquitin-dependent degradation. EMBO J. 2002;21(1–2):93–102.

    Article  PubMed  CAS  Google Scholar 

  15. Tsunematsu R, Nakayama k, Oike Y. Mouse Fbw7/Sel-10/Cdc4 is required for notch degradation during vascular development. J Biol Chem. 2004;279(10):9417–23.

    Article  PubMed  CAS  Google Scholar 

  16. Chatterjee A, Black SM, Catravas JD. Endothelial nitric oxide (NO) and its pathophysiologic regulation. Vascul Pharmacol. 2008;49(4–6):134–40.

    Article  PubMed  CAS  Google Scholar 

  17. Boo YC, Kim HJ, Song H. Coordinated regulation of endothelial nitric oxide synthase activity by phosphorylation and subcellular localization. Free Radic Biol Med. 2006;41(1):144–53.

    Article  PubMed  CAS  Google Scholar 

  18. Jiang J, Cyr D, Babbitt RW. Chaperone-dependent regulation of endothelial nitric-oxide synthase intracellular trafficking by the co-chaperone/ubiquitin ligase CHIP. J Biol Chem. 2003;278(49):49332–41.

    Article  PubMed  CAS  Google Scholar 

  19. Page CL, Noirez P, Courtya J. Exercise training improves functional post-ischemic recovery in senescent heart. Exp Gerontol. 2009;44(3):177–82.

    Article  PubMed  Google Scholar 

  20. Qi X, Okamoto Y, Murakawa T. Sustained delivery of sphingosine-1-phosphate using poly(lactic-co-glycolic acid)-based microparticles stimulates Akt/ERK-eNOS mediated angiogenesis and vascular maturation restoring blood flow in ischemic limbs of mice. Eur J Pharmacol. 2010;634(1–3):121–31.

    Article  PubMed  CAS  Google Scholar 

  21. Lanteri R, Acquaviva R, Giacomo CD. Rutin in rat liver ischemia/reperfusion injury: effect on DDAH/NOS pathway. Microsurgery. 2007;27(4):245–51.

    Article  PubMed  Google Scholar 

  22. Stangl V, Lorenz M, Meiners S. Long-term up-regulation of eNOS and improvement of endothelial function by inhibition of the ubiquitin-proteasome pathway. FASEB J. 2004;18(2):272–9.

    Article  PubMed  CAS  Google Scholar 

  23. Channon KM. Tetrahydrobiopterin: regulator of endothelial nitric oxide synthase in vascular disease. Trends Cardiovasc Med. 2004;14(8):323–7.

    Article  PubMed  CAS  Google Scholar 

  24. Kumar KS, Vijayan V, Bhaskar S. Anti-inflammatory potential of an ethyl acetate fraction isolated from Justicia gendarussa roots through inhibition of iNOS and COX-2 expression via NF-kappaB pathway. Cell Immunol. 2012;272:283–9.

    Article  PubMed  CAS  Google Scholar 

  25. Guo X, Kassab GS. Role of shear stress on nitrite and NOS protein content in different size conduit arteries of swine. Acta Physiol (Oxf). 2009;197(2):99–106.

    Article  CAS  Google Scholar 

  26. Chen L, Kong X, Fu J. CHIP facilitates ubiquitination of inducible nitric oxide synthase and promotes its proteasomal degradation. Cell Immunol. 2009;258(1):38–43.

    Article  PubMed  CAS  Google Scholar 

  27. Osawa Y, Lowe ER, Everett AC. Proteolytic degradation of nitric oxide synthase: effect of inhibitors and role of hsp90-based chaperones. J Pharmacol Exp Ther. 2003;304(2):493–7.

    Article  PubMed  CAS  Google Scholar 

  28. Meier P, Golshayan D, Blanc E. Oxidized LDL modulates apoptosis of regulatory T cells in patients with ESRD. J Am Soc Nephrol. 2009;20(6):1368–84.

    Article  PubMed  CAS  Google Scholar 

  29. Qureshi N, Vogel SN, Van Way C 3rd. The proteasome: a central regulator of inflammation and macrophage function. Immunol Res. 2005;31(3):243–60.

    Article  PubMed  CAS  Google Scholar 

  30. Marfella R, Filippo CD, Portoghese M. Proteasome activity as a target of hormone replacement therapy-dependent plaque stabilization in postmenopausal women. Hypertension. 2008;51(4):1135–41.

    Article  PubMed  CAS  Google Scholar 

  31. Tan C, Li Y, Tan X, Pan H. Inhibition of the ubiquitin-proteasome system: a new avenue for atherosclerosis. Clin Chem Lab Med. 2006;44(10):1218–25.

    Article  PubMed  CAS  Google Scholar 

  32. Liapikos TA, Antonopoulou S, Karabina SP. Platelet-activating factor formation during oxidative modification of low-density lipoprotein when PAF-acetylhydrolase has been inactivated. Biochim Biophys Acta. 1994;1212(3):353–60.

    Article  PubMed  CAS  Google Scholar 

  33. Dupré DJ, Chen Z, Gouill CL. Trafficking, ubiquitination, and down-regulation of the human platelet-activating factor receptor. J Biol Chem. 2003;278(48):48228–35.

    Article  PubMed  CAS  Google Scholar 

  34. Kovacs A, Tornvall P, Nilsson R. Human C-reactive protein slows atherosclerosis development in a mouse model with human-like hypercholesterolemia. Proc Natl Acad Sci U S A. 2007;104(34):13768–73.

    Article  PubMed  CAS  Google Scholar 

  35. Alkalay I, Yaron A, Hatzubai A. In vivo stimulation of I kappa B phosphorylation is not sufficient to activate NF-kappa B. Mol Cell Biol. 1995;15(3):1294–301.

    PubMed  CAS  Google Scholar 

  36. Alkalay I, Yaron A, Hatzubai A. Stimulation-dependent I kappa B alpha phosphorylation marks the NF-kappa B inhibitor for degradation via the ubiquitin-proteasome pathway. Proc Natl Acad Sci U S A. 1995;92(23):10599–603.

    Article  PubMed  CAS  Google Scholar 

  37. Spencer E, Jiang J, Chen ZJ. Signal-induced ubiquitination of IkappaBalpha by the F-box protein Slimb/beta-TrCP. Genes Dev. 1999;13(3):284–94.

    Article  PubMed  CAS  Google Scholar 

  38. Xiao G, Harhaj EW, Sun SC. NF-kappaB-inducing kinase regulates the processing of NF-kappaB2 p100. Mol Cell. 2001;7(2):401–9.

    Article  PubMed  CAS  Google Scholar 

  39. Wertz IE, O’Rourke KM, Zhou H. De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling. Nature. 2004;430(7000):694–9.

    Article  PubMed  CAS  Google Scholar 

  40. Haas M, Page S, Page M. Effect of proteasome inhibitors on monocytic IkappaB-alpha and -beta depletion, NF-kappaB activation, and cytokine production. J Leukoc Biol. 1998;63(3):395–404.

    PubMed  CAS  Google Scholar 

  41. Kutuk O, Basaga H. Inflammation meets oxidation: NF-kappaB as a mediator of initial lesion development in atherosclerosis. Trends Mol Med. 2003;9(12):549–57.

    Article  PubMed  CAS  Google Scholar 

  42. Okamoto H, Takaoka M, Ohkita M. A proteasome inhibitor lessens the increased aortic endothelin-1 content in deoxycorticosterone acetate-salt hypertensive rats. Eur J Pharmacol. 1998;350(1):R11–2.

    Article  PubMed  CAS  Google Scholar 

  43. Meiners S, Ludwig A, Lorenz M. Nontoxic proteasome inhibition activates a protective antioxidant defense response in endothelial cells. Free Radic Biol Med. 2006;40(12):2232–41.

    Article  PubMed  CAS  Google Scholar 

  44. Lorenz M, Wilck N, Meiners S. Proteasome inhibition prevents experimentally-induced endothelial dysfunction. Life Sci. 2009;84(25–26):929–34.

    Article  PubMed  CAS  Google Scholar 

  45. de Cavanagh EM, Ferder LF, Ferder MD. Vascular structure and oxidative stress in salt-loaded spontaneously hypertensive rats: effects of losartan and atenolol. Am J Hypertens. 2010;23(12):1318–25.

    Article  PubMed  Google Scholar 

  46. Rueckschloss U, Quinn MT, Holtz J. Dose-dependent regulation of NAD(P)H oxidase expression by angiotensin II in human endothelial cells: protective effect of angiotensin II type 1 receptor blockade in patients with coronary artery disease. Arterioscler Thromb Vasc Biol. 2002;22(11):1845–51.

    Article  PubMed  CAS  Google Scholar 

  47. Mehta PA, McDonagh S, Phillips J. Angiotensin receptor blocker therapy for heart failure patients: is combination treatment a feasible prospect? Clin Cardiol. 2009;32(9):513–8.

    Article  PubMed  CAS  Google Scholar 

  48. Verrilli MAL, Fermepín MR, Carbajosa NL. Angiotensin-(1-7) through Mas receptor upregulates neuronal norepinephrine transporter via Akt And erk1/2-dependent pathways. J Neurochem. 2012;120:46–55.

    Article  PubMed  Google Scholar 

  49. Xu J, Wang S, Wu Y. Tyrosine nitration of PA700 activates the 26S proteasome to induce endothelial dysfunction in mice with angiotensin II-induced hypertension. Hypertension. 2009;54(3):625–32.

    Article  PubMed  CAS  Google Scholar 

  50. Mbonye UR, Yuan C, Harris CE. Two distinct pathways for cyclooxygenase-2 protein degradation. J Biol Chem. 2008;283(13):8611–23.

    Article  PubMed  CAS  Google Scholar 

  51. Marchese A. Ubiquitination of chemokine receptors. Methods Enzymol. 2009;460:413–22.

    Article  PubMed  CAS  Google Scholar 

  52. Hicke L, Riezman H. Ubiquitination of a yeast plasma membrane receptor signals its ligand-stimulated endocytosis. Cell. 1996;84(2):277–87.

    Article  PubMed  CAS  Google Scholar 

  53. Nilssen LS, Odegård J, Thoresen GH. G protein-coupled receptor agonist-stimulated expression of ATF3/LRF-1 and c-myc and comitogenic effects in hepatocytes do not require EGF receptor transactivation. J Cell Physiol. 2004;201(3):349–58.

    Article  PubMed  CAS  Google Scholar 

  54. Penela P, Ribas C, Mayor Jr F. Mechanisms of regulation of the expression and function of G protein-coupled receptor kinases. Cell Signal. 2003;15(11):973–81.

    Article  PubMed  CAS  Google Scholar 

  55. Wojcikiewicz RJ. Regulated ubiquitination of proteins in GPCR-initiated signaling pathways. Trends Pharmacol Sci. 2004;25(1):35–41.

    Article  PubMed  CAS  Google Scholar 

  56. Breusing N, Grune T. Regulation of proteasome-mediated protein degradation during oxidative stress and aging. Biol Chem. 2008;389(3):203–9.

    Article  PubMed  CAS  Google Scholar 

  57. Versari D, Herrmann J, Gössl M. Dysregulation of the ubiquitin-proteasome system in human carotid atherosclerosis. Arterioscler Thromb Vasc Biol. 2006;26(9):2132–9.

    Article  PubMed  CAS  Google Scholar 

  58. Moser M, Yu Q, Bode C, Xiong JW. BMPER is a conserved regulator of hematopoietic and vascular development in zebrafish. J Mol Cell Cardiol. 2007;43(3):243–53.

    Article  PubMed  CAS  Google Scholar 

  59. Iso T, Hamamori Y, Kedes L. Notch signaling in vascular development. Arterioscler Thromb Vasc Biol. 2003;23(4):543–53.

    Article  PubMed  CAS  Google Scholar 

  60. Le Bras S, Loyer N, Le Borgne R. The multiple facets of ubiquitination in the regulation of notch signaling pathway. Traffic. 2011;12(2):149–61.

    Article  PubMed  Google Scholar 

  61. Bruns AF, Bao L, Walker JH, Ponnambalam S. VEGF-A-stimulated signalling in endothelial cells via a dual receptor tyrosine kinase system is dependent on co-ordinated trafficking and proteolysis. Biochem Soc Trans. 2009;37(Pt 6):1193–7.

    Article  PubMed  CAS  Google Scholar 

  62. Goedeke L, Fernandez-Hernando C. Regulation of cholesterol homeostasis. Cell Mol Life Sci. 2012;69:915–30.

    Article  PubMed  CAS  Google Scholar 

  63. Paul A, Chan L. Adipose differentiation related protein: a possible target for the prevention and treatment of atherosclerosis, in metabolic defects in atherosclerosis. Circulation. 2006;114:II_25.

    Article  Google Scholar 

  64. Feingold KR, Kazemi MR, Magra AL. ADRP/ADFP and Mal1 expression are increased in macrophages treated with TLR agonists. Atherosclerosis. 2010;209(1):81–8.

    Article  PubMed  CAS  Google Scholar 

  65. Masuda Y, Itabe H, Odaki M. ADRP/adipophilin is degraded through the proteasome-dependent pathway during regression of lipid-storing cells. J Lipid Res. 2006;47(1):87–98.

    Article  PubMed  CAS  Google Scholar 

  66. Paul A, Chang BH, Li L. Deficiency of adipose differentiation-related protein impairs foam cell formation and protects against atherosclerosis. Circ Res. 2008;102(12):1492–501.

    Article  PubMed  CAS  Google Scholar 

  67. Barringhaus KG, Matsumura ME. The proteasome inhibitor lactacystin attenuates growth and migration of vascular smooth muscle cells and limits the response to arterial injury. Exp Clin Cardiol. 2007;12(3):119–24.

    PubMed  CAS  Google Scholar 

  68. Zhang F, Laiho M. On and off: proteasome and TGF-beta signaling. Exp Cell Res. 2003;291(2):275–81.

    Article  PubMed  CAS  Google Scholar 

  69. Meiners S, Hocher B, Weller A. Downregulation of matrix metalloproteinases and collagens and suppression of cardiac fibrosis by inhibition of the proteasome. Hypertension. 2004;44(4):471–7.

    Article  PubMed  CAS  Google Scholar 

  70. Herrmann J, Lerman LO, Mukhopadhya D. Angiogenesis in atherogenesis. Arterioscler Thromb Vasc Biol. 2006;26(9):1948–57.

    Article  PubMed  CAS  Google Scholar 

  71. Bruick RK, McKnight SL. A conserved family of prolyl-4-hydroxylases that modify HIF. Science. 2001;294(5545):1337–40.

    Article  PubMed  CAS  Google Scholar 

  72. Pappalardi MB, McNulty DE, Martin JD. Biochemical characterization of human HIF hydroxylases using HIF protein substrates that contain all three hydroxylation sites. Biochem J. 2011;436(2):363–9.

    Article  PubMed  CAS  Google Scholar 

  73. von der Thusen JH, van Vlijmen BJ, Hoeben RC. Induction of atherosclerotic plaque rupture in apolipoprotein E−/− mice after adenovirus-mediated transfer of p53. Circulation. 2002;105(17):2064–70.

    Article  PubMed  Google Scholar 

  74. Lee DH, Goldberg AL. Proteasome inhibitors: valuable new tools for cell biologists. Trends Cell Biol. 1998;8(10):397–403.

    Article  PubMed  CAS  Google Scholar 

  75. Kim SS, Rhee S, Lee KH. Inhibitors of the proteasome block the myogenic differentiation of rat L6 myoblasts. FEBS Lett. 1998;433(1–2):47–50.

    Article  PubMed  CAS  Google Scholar 

  76. Lee DH, Goldberg AL. Proteasome inhibitors cause induction of heat shock proteins and trehalose, which together confer thermotolerance in Saccharomyces cerevisiae. Mol Cell Biol. 1998;18(1):30–8.

    PubMed  CAS  Google Scholar 

  77. Herrmann J, Ciechanover A, Lerman LO. The ubiquitin-proteasome system—micro target for macro intervention? Int J Cardiovasc Intervent. 2005;7(1):5–13.

    PubMed  Google Scholar 

  78. Herrmann J, Ciechanover A, Lerman LO. The ubiquitin-proteasome system in cardiovascular diseases—a hypothesis extended. Cardiovasc Res. 2004;61(1):11–21.

    Article  PubMed  CAS  Google Scholar 

  79. Myung J, Kim KB, Crews CM. The ubiquitin-proteasome pathway and proteasome inhibitors. Med Res Rev. 2001;21(4):245–73.

    Article  PubMed  CAS  Google Scholar 

  80. Aghajanian C, Soignet S, Dizon DS. A phase I trial of the novel proteasome inhibitor PS341 in advanced solid tumor malignancies. Clin Cancer Res. 2002;8(8):2505–11.

    PubMed  CAS  Google Scholar 

  81. Dy GK, Thomas JP, Wilding G, Bruzek L. A phase I and pharmacologic trial of two schedules of the proteasome inhibitor, PS-341 (bortezomib, velcade), in patients with advanced cancer. Clin Cancer Res. 2005;11(9):3410–6.

    Article  PubMed  CAS  Google Scholar 

  82. Papandreou CN, Daliani DD, Nix D. Phase I trial of the proteasome inhibitor bortezomib in patients with advanced solid tumors with observations in androgen-independent prostate cancer. J Clin Oncol. 2004;22(11):2108–21.

    Article  PubMed  CAS  Google Scholar 

  83. Orlowski RZ, Stinchcombe TE, Mitchell BS. Phase I trial of the proteasome inhibitor PS-341 in patients with refractory hematologic malignancies. J Clin Oncol. 2002;20(22):4420–7.

    Article  PubMed  CAS  Google Scholar 

  84. Richardson PG, Sonneveld P, Schuster MW. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med. 2005;352(24):2487–98.

    Article  PubMed  CAS  Google Scholar 

  85. Khan ML, Reeder CB, Kumar S. A comparison of lenalidomide/dexamethasone versus cyclophosphamide/lenalidomide/dexamethasone versus cyclophosphamide/bortezomib/dexamethasone in newly diagnosed multiple myeloma. Br J Haematol. 2012;156:326–33.

    Article  PubMed  CAS  Google Scholar 

  86. Adams J, Palombella VJ, Elliott PJ. Proteasome inhibition: a new strategy in cancer treatment. Invest New Drugs. 2000;18(2):109–21.

    Article  PubMed  CAS  Google Scholar 

  87. Herrmann J, Saguner AM, Versari D. Chronic proteasome inhibition contributes to coronary atherosclerosis. Circ Res. 2007;101(9):865–74.

    Article  PubMed  CAS  Google Scholar 

  88. Meiners S, Laule M, Rother W. Ubiquitin-proteasome pathway as a new target for the prevention of restenosis. Circulation. 2002;105(4):483–9.

    Article  PubMed  CAS  Google Scholar 

  89. Thyberg J, Blomgren K. Effects of proteasome and calpain inhibitors on the structural reorganization and proliferation of vascular smooth muscle cells in primary culture. Lab Invest. 1999;79(9):1077–88.

    PubMed  CAS  Google Scholar 

  90. Huang YC, Chuang LY, Hung WC. Mechanisms underlying nonsteroidal anti-inflammatory drug-induced p27(Kip1) expression. Mol Pharmacol. 2002;62(6):1515–21.

    Article  PubMed  CAS  Google Scholar 

  91. Wang S, Zhang M, Liang B. AMPKalpha2 deletion causes aberrant expression and activation of NAD(P)H oxidase and consequent endothelial dysfunction in vivo: role of 26S proteasomes. Circ Res. 2010;106(6):1117–28.

    Article  PubMed  CAS  Google Scholar 

  92. Schulz E, Anter E, Zou MH. Estradiol-mediated endothelial nitric oxide synthase association with heat shock protein 90 requires adenosine monophosphate-dependent protein kinase. Circulation. 2005;111(25):3473–80.

    Article  PubMed  CAS  Google Scholar 

  93. Davis BJ, Xie Z, Viollet B. Activation of the AMP-activated kinase by antidiabetes drug metformin stimulates nitric oxide synthesis in vivo by promoting the association of heat shock protein 90 and endothelial nitric oxide synthase. Diabetes. 2006;55(2):496–505.

    Article  PubMed  CAS  Google Scholar 

  94. Zou MH, Hou XY, Shi CM. Modulation by peroxynitrite of Akt- and AMP-activated kinase-dependent Ser1179 phosphorylation of endothelial nitric oxide synthase. J Biol Chem. 2002;277(36):32552–7.

    Article  PubMed  CAS  Google Scholar 

  95. Chen Z, Peng IC, Sun W. AMP-activated protein kinase functionally phosphorylates endothelial nitric oxide synthase Ser633. Circ Res. 2009;104(4):496–505.

    Article  PubMed  CAS  Google Scholar 

  96. Wang S, Xu J, Song P. In vivo activation of AMP-activated protein kinase attenuates diabetes-enhanced degradation of GTP cyclohydrolase I. Diabetes. 2009;58(8):1893–901.

    Article  PubMed  CAS  Google Scholar 

  97. Rockwell P, Yuan H, Magnusson R. Proteasome inhibition in neuronal cells induces a proinflammatory response manifested by upregulation of cyclooxygenase-2, its accumulation as ubiquitin conjugates, and production of the prostaglandin PGE(2). Arch Biochem Biophys. 2000;374(2):325–33.

    Article  PubMed  CAS  Google Scholar 

  98. Meng L, Mohan R, Kwok BHB. Epoxomicin, a potent and selective proteasome inhibitor, exhibits in vivo antiinflammatory activity. Proc Natl Acad Sci U S A. 1999;96(18):10403–8.

    Article  PubMed  CAS  Google Scholar 

  99. Richardson PG, Barlogie B, Berenson J. Clinical factors predictive of outcome with bortezomib in patients with relapsed, refractory multiple myeloma. Blood. 2005;106(9):2977–81.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

Dr. Ming-Hui Zou’s laboratory is supported by NIH grants (HL079584, HL080499, HL074399, HL089920, HL096032, and HL105157), a grant-in-aid from the Juvenile Diabetes Research foundation, a Research Award from the Oklahoma Center for the Advancement of Science and Technology (OCAST), a Research Award from the American Diabetes Association, and funds from the Warren Chair of the University of Oklahoma Health Science Center. Dr. Zou is a recipient of the National Established Investigator award of American Heart Association.

Author information

Authors and Affiliations

  1. Department of Medicine, University of Oklahoma Health Sciences Center, 941 Stanton L Young Boulevard, BSEB Room 306A, Oklahoma City, OK, 73104, USA

    Najeeb A. Shirwany MD, PhD & Ming-Hui Zou MD, PhD

Authors
  1. Najeeb A. Shirwany MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ming-Hui Zou MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ming-Hui Zou MD, PhD .

Editor information

Editors and Affiliations

  1. , The University of North Carolina, McAllister Heart Institute, 101 Manning Drive, Chapel Hill, 27599-7525, USA

    Jonathon W. Homeister

  2. , The University of North Carolina, McAllister Heart Institute, 103 Mason Farm Road, Chapel Hill, 27599-7525, USA

    Monte S. Willis

Rights and permissions

Reprints and permissions

Copyright information

© 2012 Springer Science+Business Media New York

About this chapter

Cite this chapter

Shirwany, N.A., Zou, MH. (2012). The Ubiquitin Proteasome System in Endothelial Cell Dysfunction and Vascular Disease. In: Homeister, J., Willis, M. (eds) Molecular and Translational Vascular Medicine. Molecular and Translational Medicine. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-61779-906-8_4

Download citation

  • DOI: https://doi.org/10.1007/978-1-61779-906-8_4

  • Published:

  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-61779-905-1

  • Online ISBN: 978-1-61779-906-8

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation