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Vascular Aging: Revealing the Role and Clinical Perspectives of the Urokinase System

  • Yulia KiyanEmail author
  • Bianca Fuhrman
  • Hermann Haller
  • Inna Dumler
Chapter
Part of the International Perspectives on Aging book series (Int. Perspect. Aging, volume 10)

Abstract

Cardiovascular diseases (CVD) are the most common cause of death among the elderly population in Western countries. Despite progress in managing some of the established risk factors like hypertension and hypercholesterolemia, the incidence of CVD is predicted to increase as the population ages. The aging process itself is associated with morphological and functional changes in the vasculature. Moreover, age-related changes render the cardiovascular system susceptible to damaging actions of risk factors and diseases. Vascular smooth muscle cells (VSMCs) are intrinsically involved in age-associated changes of the vasculature. With age, the VSMC phenotype shifts towards a pathophysiological synthetic phenotype characterized by migration, proliferation, release of inflammatory cytokines, and augmented extracellular matrix deposition. The molecular mechanisms underlying age-associated VSMC phenotypic changes remain unclear. Recent large-scale population studies showed a close correlation between the urokinase/urokinase receptor system and CVD, inflammation, aging, and mortality. In our research, we have identified a new link between the urokinase system and arterial wall changes during vascular remodeling and initiation/progression of atherosclerosis. The urokinase system exerts its function at different levels. Systemically, it modulates oxidative stress via regulation of paraoxonase 1 production by the liver. Locally in the blood vessel wall, the urokinase system modulates VSMCs towards the synthetic phenotype via proteasomal degradation of the transcription coactivator, myocardin. Furthermore, the urokinase system interferes with VSMC senescence that influences the outcome of vascular remodeling and the fate of atherosclerotic plaques. The variety of functions exerted by the urokinase system in the vascular wall makes it an attractive therapeutic target.

Keywords

Vascular Remodel Proteasomal Degradation Serum Response Factor Contractile Phenotype VSMC Proliferation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

We would like to thank Dr. K. Grote for his comments on an earlier draft of the manuscript. This work was supported by an ERA-AGE FLARE grant, financed by Bundesministerium für Bildung und Forschung [01 ET 0802]; grant P59/10//A101/10 from Else Kroener-Fresenius-Stiftung; grants from the Deutsche Forschungsgemeinschaft [KI 1376/2-1 and KI 1367/2-2; DU 344/7-1] and from the Deutscher Akademischer Austausch Dienst [A/08/98019]; and Israel Science Foundation Grant 669/09, funded by the Israel Academy of Sciences and Humanities.

References

  1. Aharoni S, Aviram M, Fuhrman B (2013) Paraoxonase 1 (PON1) reduces macrophage inflammatory responses. Atherosclerosis 228(2):353–361CrossRefGoogle Scholar
  2. Antoniades C, Antonopoulos AS, Bendall JK, Channon KM (2009) Targeting redox signaling in the vascular wall: from basic science to clinical practice. Curr Pharm Des 15(3):329–342CrossRefGoogle Scholar
  3. Asuthkar S, Gondi C, Nalla A, Velpula K, Gorantla B, Rao J (2012) Urokinase-type plasminogen activator receptor (uPAR)-mediated regulation of WNT/a-catenin signaling is enhanced in irradiated medulloblastoma cells. J Biol Chem 287(24):20576–20589CrossRefGoogle Scholar
  4. Binder BR, Mihaly J, Prager GW (2007) uPAR-uPA-PAI-1 interactions and signaling: a vascular biologist’s view. Thromb Haemost 97(3):336–342Google Scholar
  5. Blasi F, Carmeliet P (2002) uPAR: a versatile signalling orchestrator. Nat Rev Mol Cell Biol 3(12):932–943CrossRefGoogle Scholar
  6. Campisi J, d’Adda di Fagagna F (2007) Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol 8(9):729–740CrossRefGoogle Scholar
  7. Chen J, Kitchen CM, Streb JW, Miano JM (2002) Myocardin: a component of a molecular switch for smooth muscle differentiation. J Mol Cell Cardiol 34(10):1345–1356CrossRefGoogle Scholar
  8. Cole JE, Georgiou E, Monaco C (2010) The expression and functions of toll-like receptors in atherosclerosis. Mediators Inflamm 2010:393946CrossRefGoogle Scholar
  9. Coppe JP, Desprez PY, Krtolica A, Campisi J (2010) The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol 5:99–118CrossRefGoogle Scholar
  10. Davis-Dusenbery BN, Wu C, Hata A (2011) Micromanaging vascular smooth muscle cell differentiation and phenotypic modulation. Arterioscler Thromb Vasc Biol 31(11):2370–2377CrossRefGoogle Scholar
  11. Dumler I, Weis A, Mayboroda OA, Maasch C, Jerke U, Haller H, Gulba DC (1998) The Jak/Stat pathway and urokinase receptor signaling in human aortic vascular smooth muscle cells. J Biol Chem 273(1):315–321CrossRefGoogle Scholar
  12. El Assar M, Angulo J, Vallejo S, Peiro C, Sanchez-Ferrer CF, Rodriguez-Manas L (2012) Mechanisms involved in the aging-induced vascular dysfunction. Front Physiol 3:132CrossRefGoogle Scholar
  13. Ellam TJ, Chico TJ (2012) Phosphate: the new cholesterol? The role of the phosphate axis in non-uremic vascular disease. Atherosclerosis 220(2):310–318CrossRefGoogle Scholar
  14. Fuhrman B, Partoush A, Volkova N, Aviram M (2008) Ox-LDL induces monocyte-to-macrophage differentiation in vivo: Possible role for the macrophage colony stimulating factor receptor (M-CSF-R). Atherosclerosis 196(2):598–607CrossRefGoogle Scholar
  15. Gomez D, Owens GK (2012) Smooth muscle cell phenotypic switching in atherosclerosis. Cardiovasc Res 95(2):156–164CrossRefGoogle Scholar
  16. Heidenreich PA, Trogdon JG, Khavjou OA, Butler J, Dracup K, Ezekowitz MD, Finkelstein EA, Hong Y, Johnston SC, Khera A, Lloyd-Jones DM, Nelson SA, Nichol G, Orenstein D, Wilson PW, Woo YJ (2011) Forecasting the future of cardiovascular disease in the United States: a policy statement from the American Heart Association. Circulation 123(8):933–944CrossRefGoogle Scholar
  17. Heistad DD, Wakisaka Y, Miller J, Chu Y, Pena-Silva R (2009) Novel aspects of oxidative stress in cardiovascular diseases. Circ J 73(2):201–207CrossRefGoogle Scholar
  18. Herrmann J, Lerman LO, Lerman A (2010) On to the road to degradation: atherosclerosis and the proteasome. Cardiovasc Res 85(2):291–302CrossRefGoogle Scholar
  19. Hodjat M, Haller H, Dumler I, Kiyan Y (2013) Urokinase receptor mediates doxorubicin induced vascular smooth muscle cells senescence via proteasomal degradation of TRF2. J Vasc Res 50(2):109–123CrossRefGoogle Scholar
  20. Karagiannis GS, Weile J, Bader GD, Minta J (2013) Integrative pathway dissection of molecular mechanisms of moxLDL-induced vascular smooth muscle phenotype transformation. BMC Cardiovasc Disord 13:4CrossRefGoogle Scholar
  21. Khateeb J, Kiyan Y, Aviram M, Tkachuk S, Dumler I, Fuhrman B (2012) Urokinase-type plasminogen activator downregulates paraoxonase 1 expression in hepatocytes by stimulating peroxisome proliferator-activated receptor-gamma nuclear export. Arterioscler Thromb Vasc Biol 32(2):449–458CrossRefGoogle Scholar
  22. Kiian I, Tkachuk N, Haller H, Dumler I (2003) Urokinase-induced migration of human vascular smooth muscle cells requires coupling of the small GTPases RhoA and Rac1 to the Tyk2/PI3-K signalling pathway. Thromb Haemost 89(5):904–914Google Scholar
  23. Kiyan Y, Kiyan R, Haller H, Dumler I (2005) Urokinase-induced signaling in human vascular smooth muscle cells are mediated by PDGFR-ß. EMBO J 24(10):1787–1797CrossRefGoogle Scholar
  24. Kiyan J, Smith G, Haller H, Dumler I (2009) Urokinase receptor-mediated phenotypic changes of vascular smooth muscle cells require involvement of membrane rafts. Biochem J 423(3): 343–351CrossRefGoogle Scholar
  25. Kiyan Y, Limbourg A, Kiyan R, Tkachuk S, Limbourg F, Ovsianikov A, Chichkov B, Haller H, Dumler I (2012) Urokinase receptor associates with myocardin to control vascular smooth muscle cells phenotype in vascular disease. Arterioscler Thromb Vasc Biol 32(1):110–122CrossRefGoogle Scholar
  26. Krug AW, Allenhofer L, Monticone R, Spinetti G, Gekle M, Wang M, Lakatta EG (2010) Elevated mineralocorticoid receptor activity in aged rat vascular smooth muscle cells promotes a proinflammatory phenotype via extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase and epidermal growth factor receptor-dependent pathways. Hypertension 55(6): 1476–1483CrossRefGoogle Scholar
  27. Lacolley P, Regnault V, Nicoletti A, Li Z, Michel JB (2012) The vascular smooth muscle cell in arterial pathology: a cell that can take on multiple roles. Cardiovasc Res 95(2):194–204CrossRefGoogle Scholar
  28. Lyngbaek S, Marott JL, Sehestedt T, Hansen TW, Olsen MH, Andersen O, Linneberg A, Haugaard SB, Eugen-Olsen J, Hansen PR, Jeppesen J (2012) Cardiovascular risk prediction in the general population with use of suPAR, CRP, and Framingham Risk Score. Int J Cardiol 167(6): 2904–2911CrossRefGoogle Scholar
  29. Maejima Y, Adachi S, Ito H, Hirao K, Isobe M (2008) Induction of premature senescence in cardiomyocytes by doxorubicin as a novel mechanism of myocardial damage. Aging Cell 7(2):125–136CrossRefGoogle Scholar
  30. Mahmoudi M, Gorenne I, Mercer J, Figg N, Littlewood T, Bennett M (2008) Statins use a novel Nijmegen breakage syndrome-1-dependent pathway to accelerate DNA repair in vascular smooth muscle cells. Circ Res 103(7):717–725CrossRefGoogle Scholar
  31. Mazar AP, Ahn RW, O’Halloran TV (2011) Development of novel therapeutics targeting the urokinase plasminogen activator receptor (uPAR) and their translation toward the clinic. Curr Pharm Des 17(19):1970–1978CrossRefGoogle Scholar
  32. North BJ, Sinclair DA (2012) The intersection between aging and cardiovascular disease. Circ Res 110(8):1097–1108CrossRefGoogle Scholar
  33. O’Halloran TV, Ahn R, Hankins P, Swindell E, Mazar AP (2013) The many spaces of uPAR: delivery of theranostic agents and nanobins to multiple tumor compartments through a single target. Theranostics 3(7):496–506CrossRefGoogle Scholar
  34. Orr AW, Hastings NE, Blackman BR, Wamhoff BR (2010) Complex regulation and function of the inflammatory smooth muscle cell phenotype in atherosclerosis. J Vasc Res 47(2):168–180CrossRefGoogle Scholar
  35. Padro T, Pena E, Garcia-Arguinzonis M, Llorente-Cortes V, Badimon L (2008) Low-density lipoproteins impair migration of human coronary vascular smooth muscle cells and induce changes in the proteomic profile of myosin light chain. Cardiovasc Res 77(1):211–220CrossRefGoogle Scholar
  36. Pidkovka N, Cherepanova O, Yoshida T, Alexander M, Deaton R, Thomas J, Leitinger N, Owens G (2007) Oxidized phospholipids induce phenotypic switching of vascular smooth muscle cells in vivo and in vitro. Circ Res 101(8):792–801CrossRefGoogle Scholar
  37. Pillay V, Dass C, Choong F (2006) The urokinase plasminogen activator receptor as a gene therapy target for cancer. Trends Biotechnol 25(1):33–39CrossRefGoogle Scholar
  38. Rabbani SA, Gladu J (2002) Urokinase receptor antibody can reduce tumor volume and detect the presence of occult tumor metastases in vivo. Cancer Res 62(8):2390–2397Google Scholar
  39. Rong JX, Shapiro M, Trogan E, Fisher EA (2003) Transdifferentiation of mouse aortic smooth muscle cells to a macrophage-like state after cholesterol loading. Proc Natl Acad Sci U S A 100(23):13531–13536CrossRefGoogle Scholar
  40. Smith H, Marshall C (2010) Regulation of cell signalling by uPAR. Nat Rev Mol Cell Biol 11(1):23–36CrossRefGoogle Scholar
  41. Wang JC, Bennett M (2012) Aging and atherosclerosis: mechanisms, functional consequences, and potential therapeutics for cellular senescence. Circ Res 111(2):245–259CrossRefGoogle Scholar
  42. Wang D, Chang PS, Wang Z, Sutherland L, Richardson JA, Small E, Krieg PA, Olson EN (2001) Activation of cardiac gene expression by myocardin, a transcriptional cofactor for serum response factor. Cell 105(7):851–862CrossRefGoogle Scholar
  43. Wu X, Zhou Q, Huang L, Sun A, Wang K, Zou Y, Ge J (2008) Ageing-exaggerated proliferation of vascular smooth muscle cells is related to attenuation of Jagged1 expression in endothelial cells. Cardiovasc Res 77(4):800–808CrossRefGoogle Scholar
  44. Xie P, Fan Y, Zhang H, Zhang Y, Mingpeng S, Gu D, Patterson C, Li H (2009) CHIP represses myocardin-induced smooth muscle cell differentiation via ubiquitin-mediated proteasomal degradation. Mol Cell Biol 29(9):2398–2408CrossRefGoogle Scholar
  45. Yoshida T, Gan Q, Owens GK (2008) Kruppel-like factor 4, Elk-1, and histone deacetylases cooperatively suppress smooth muscle cell differentiation markers in response to oxidized phospholipids. Am J Physiol Cell Physiol 295(5):C1175–C1182CrossRefGoogle Scholar
  46. Zheng B, Han M, Wen JK (2010) Role of Kruppel-like factor 4 in phenotypic switching and proliferation of vascular smooth muscle cells. IUBMB Life 62(2):132–139Google Scholar

Copyright information

© Springer International Publishing Switzerland 2014

Authors and Affiliations

  • Yulia Kiyan
    • 1
    Email author
  • Bianca Fuhrman
    • 2
  • Hermann Haller
    • 1
  • Inna Dumler
    • 1
  1. 1.Department of NephrologyHannover Medical SchoolHannoverGermany
  2. 2.The Lipid Research LaboratoryTechnion Faculty of Medicine and Rambam Medical CenterHaifaIsrael

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