Skip to main content
SpringerLink
Log in

Endothelial Mitochondria: Contribution to Cardiovascular Function and Disease

  • Chapter
  • First Online:
Mitochondria and Their Role in Cardiovascular Disease

  • 1802 Accesses

Abstract

ATP supplies in endothelial cells are relatively independent of mitochondrial oxidative pathways. Endothelial mitochondria emerge as agents with roles in modulating the dynamics of intracellular calcium and the generation of reactive oxygen species (ROS) and nitric oxide (NO). Oxidative stress and ischemia provoke an opening of the mitochondrial permeability transition pore and activation of mitochondrial pathways of apoptosis which compromises survival of endothelial cells. Impairment of mitochondrial function contributes to the development of endothelial dysfunction leading eventually to several diseases, such as atherosclerosis, diabetes, heart failure, and reperfusion injury associated with ischemia.

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 139.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 179.99
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. Moncada S, Palmer RM, Higgs EA. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev. 1991;43(2): 109–42.

    PubMed  CAS  Google Scholar 

  2. Griffith TM, Edwards DH, Newby AC, Lewis MJ, Henderson AH. Production of endothelium derived relaxant factor is dependent on oxidative phosphorylation and extracellular calcium. Cardiovasc Res. 1986;20(1):7–12.

    Article  PubMed  CAS  Google Scholar 

  3. Newby AC, Henderson AH. Stimulus-secretion coupling in vascular endothelial cells. Annu Rev Physiol. 1990;52:661–74.

    Article  PubMed  CAS  Google Scholar 

  4. Wood PG, Gillespie JI. Evidence for mitochondrial Ca(2+)-induced Ca2+ release in permeabilised endothelial cells. Biochem Biophys Res Commun. 1998;246(2):543–8.

    Article  PubMed  CAS  Google Scholar 

  5. Lawrie AM, Rizzuto R, Pozzan T, Simpson AW. A role for calcium influx in the regulation of mitochondrial calcium in endothelial cells. J Biol Chem. 1996;271(18):10753–9.

    Article  PubMed  CAS  Google Scholar 

  6. Malli R, Frieden M, Osibow K, et al. Sustained Ca2+ transfer across mitochondria is Essential for mitochondrial Ca2+ buffering, ­sore-operated Ca2+ entry, and Ca2+ store refilling. J Biol Chem. 2003;278(45):44769–79.

    Article  PubMed  CAS  Google Scholar 

  7. Rizzuto R, Brini M, Murgia M, Pozzan T. Microdomains with high Ca2+ close to IP3-sensitive channels that are sensed by neighboring mitochondria. Science. 1993;262(5134):744–7.

    Article  PubMed  CAS  Google Scholar 

  8. Rizzuto R, Bastianutto C, Brini M, Murgia M, Pozzan T. Mitochondrial Ca2+ homeostasis in intact cells. J Cell Biol. 1994;126(5):1183–94.

    Article  PubMed  CAS  Google Scholar 

  9. Hajnoczky G, Robb-Gaspers LD, Seitz MB, Thomas AP. Decoding of cytosolic calcium oscillations in the mitochondria. Cell. 1995;82(3):415–24.

    Article  PubMed  CAS  Google Scholar 

  10. Dagher Z, Ruderman N, Tornheim K, Ido Y. Acute regulation of fatty acid oxidation and amp-activated protein kinase in human umbilical vein endothelial cells. Circ Res. 2001;88(12):1276–82.

    Article  PubMed  CAS  Google Scholar 

  11. O’Malley Y, Fink BD, Ross NC, Prisinzano TE, Sivitz WI. Reactive oxygen and targeted antioxidant administration in endothelial cell mitochondria. J Biol Chem. 2006;281(52):39766–75.

    Article  PubMed  Google Scholar 

  12. Therade-Matharan S, Laemmel E, Carpentier S, et al. Reactive oxygen species production by mitochondria in endothelial cells exposed to reoxygenation after hypoxia and glucose depletion is mediated by ceramide. Am J Physiol Regul Integr Comp Physiol. 2005;289(6):R1756–62.

    Article  PubMed  CAS  Google Scholar 

  13. Mukherjee TK, Mukhopadhyay S, Hoidal JR. The role of reactive oxygen species in TNFalpha-dependent expression of the receptor for advanced glycation end products in human umbilical vein endothelial cells. Biochim Biophys Acta. 2005;1744(2):213–23.

    Article  PubMed  CAS  Google Scholar 

  14. Liu Y, Zhao H, Li H, Kalyanaraman B, Nicolosi AC, Gutterman DD. Mitochondrial sources of H2O2 generation play a key role in flow-mediated dilation in human coronary resistance arteries. Circ Res. 2003;93(6):573–80.

    Article  PubMed  CAS  Google Scholar 

  15. Zima AV, Blatter LA. Redox regulation of cardiac calcium channels and transporters. Cardiovasc Res. 2006;71(2):310–21.

    Article  PubMed  CAS  Google Scholar 

  16. Zanetti M, Katusic ZS, O’Brien T. Adenoviral-mediated overexpression of catalase inhibits endothelial cell proliferation. Am J Physiol Heart Circ Physiol. 2002;283(6):H2620–6.

    PubMed  CAS  Google Scholar 

  17. Roy S, Khanna S, Nallu K, Hunt TK, Sen CK. Dermal wound healing is subject to redox control. Mol Ther. 2006;13(1):211–20.

    Article  PubMed  CAS  Google Scholar 

  18. Polytarchou C, Papadimitriou E. Antioxidants inhibit human endothelial cell functions through down-regulation of endothelial nitric oxide synthase activity. Eur J Pharmacol. 2005;510(1–2): 31–8.

    Article  PubMed  CAS  Google Scholar 

  19. Yasuda M, Ohzeki Y, Shimizu S, et al. Stimulation of in vitro angiogenesis by hydrogen peroxide and the relation with ETS-1 in endothelial cells. Life Sci. 1999;64(4):249–58.

    Article  PubMed  CAS  Google Scholar 

  20. Chen K, Thomas SR, Albano A, Murphy MP, Keaney Jr JF. Mitochondrial function is required for hydrogen peroxide-induced growth factor receptor transactivation and downstream signaling. J Biol Chem. 2004;279(33):35079–86.

    Article  PubMed  CAS  Google Scholar 

  21. Chang TS, Cho CS, Park S, Yu S, Kang SW, Rhee SG. Peroxiredoxin III, a mitochondrion-specific peroxidase, regulates apoptotic signaling by mitochondria. J Biol Chem. 2004;279(40):41975–84.

    Article  PubMed  CAS  Google Scholar 

  22. Zhang R, Al-Lamki R, Bai L, et al. Thioredoxin-2 inhibits mitochondria-located ASK1-mediated apoptosis in a JNK-independent manner. Circ Res. 2004;94(11):1483–91.

    Article  PubMed  CAS  Google Scholar 

  23. Pueyo ME, Gonzalez W, Nicoletti A, Savoie F, Arnal JF, Michel JB. Angiotensin II stimulates endothelial vascular cell adhesion molecule-1 via nuclear factor-kappaB activation induced by intracellular oxidative stress. Arterioscler Thromb Vasc Biol. 2000;20(3):645–51.

    Article  PubMed  CAS  Google Scholar 

  24. Deshpande SS, Angkeow P, Huang J, Ozaki M, Irani K. Rac1 inhibits TNF-alpha-induced endothelial cell apoptosis: dual regulation by reactive oxygen species. FASEB J. 2000;14(12):1705–14.

    Article  PubMed  CAS  Google Scholar 

  25. Goossens V, Grooten J, De Vos K, Fiers W. Direct evidence for tumor necrosis factor-induced mitochondrial reactive oxygen intermediates and their involvement in cytotoxicity. Proc Natl Acad Sci USA. 1995;92(18):8115–9.

    Article  PubMed  CAS  Google Scholar 

  26. Yamagishi SI, Edelstein D, Du XL, Kaneda Y, Guzman M, Brownlee M. Leptin induces mitochondrial superoxide production and monocyte chemoattractant protein-1 expression in aortic endothelial cells by increasing fatty acid oxidation via protein kinase A. J Biol Chem. 2001;276(27):25096–100.

    Article  PubMed  CAS  Google Scholar 

  27. Chien S, Li S, Shyy YJ. Effects of mechanical forces on signal transduction and gene expression in endothelial cells. Hypertension. 1998;31(1 Pt 2):162–9.

    Article  PubMed  CAS  Google Scholar 

  28. Ali MH, Mungai PT, Schumacker PT. Stretch-induced phosphorylation of focal adhesion kinase in endothelial cells: role of mitochondrial oxidants. Am J Physiol Lung Cell Mol Physiol. 2006;291(1):L38–45.

    Article  PubMed  CAS  Google Scholar 

  29. Ali MH, Pearlstein DP, Mathieu CE, Schumacker PT. Mitochondrial requirement for endothelial responses to cyclic strain: implications for mechanotransduction. Am J Physiol Lung Cell Mol Physiol. 2004;287(3):L486–96.

    Article  PubMed  CAS  Google Scholar 

  30. Dhanasekaran A, Kotamraju S, Kalivendi SV, et al. Supplementation of endothelial cells with mitochondria-targeted antioxidants inhibit peroxide-induced mitochondrial iron uptake, oxidative damage, and apoptosis. J Biol Chem. 2004;279(36):37575–87.

    Article  PubMed  CAS  Google Scholar 

  31. Zmijewski JW, Moellering DR, Le Goffe C, Landar A, Ramachandran A, Darley-Usmar VM. Oxidized LDL induces mitochondrially associated reactive oxygen/nitrogen species formation in endothelial cells. Am J Physiol Heart Circ Physiol. 2005;289(2):H852–61.

    Article  PubMed  CAS  Google Scholar 

  32. Watanabe N, Zmijewski JW, Takabe W, et al. Activation of mitogen-activated protein kinases by lysophosphatidylcholine-induced mitochondrial reactive oxygen species generation in endothelial cells. Am J Pathol. 2006;168(5):1737–48.

    Article  PubMed  CAS  Google Scholar 

  33. Uchida K, Shiraishi M, Naito Y, Torii Y, Nakamura Y, Osawa T. Activation of stress signaling pathways by the end product of lipid peroxidation. 4-hydroxy-2-nonenal is a potential inducer of intracellular peroxide production. J Biol Chem. 1999;274(4):2234–42.

    Article  PubMed  CAS  Google Scholar 

  34. Humphries KM, Szweda LI. Selective inactivation of alpha-ketoglutarate dehydrogenase and pyruvate dehydrogenase: reaction of lipoic acid with 4-hydroxy-2-nonenal. Biochemistry. 1998;37(45): 15835–41.

    Article  PubMed  CAS  Google Scholar 

  35. Humphries KM, Yoo Y, Szweda LI. Inhibition of NADH-linked mitochondrial respiration by 4-hydroxy-2-nonenal. Biochemistry. 1998;37(2):552–7.

    Article  PubMed  CAS  Google Scholar 

  36. Chandel NS, Maltepe E, Goldwasser E, Mathieu CE, Simon MC, Schumacker PT. Mitochondrial reactive oxygen species trigger hypoxia-induced transcription. Proc Natl Acad Sci USA. 1998;95(20):11715–20.

    Article  PubMed  CAS  Google Scholar 

  37. Quintero M, Colombo SL, Godfrey A, Moncada S. Mitochondria as signaling organelles in the vascular endothelium. Proc Natl Acad Sci USA. 2006;103(14):5379–84.

    Article  PubMed  CAS  Google Scholar 

  38. Ido Y, Carling D, Ruderman N. Hyperglycemia-induced apoptosis in human umbilical vein endothelial cells: inhibition by the AMP-activated protein kinase activation. Diabetes. 2002;51(1):159–67.

    Article  PubMed  CAS  Google Scholar 

  39. Russell 3rd RR, Li J, Coven DL, et al. AMP-activated protein kinase mediates ischemic glucose uptake and prevents postischemic cardiac dysfunction, apoptosis, and injury. J Clin Invest. 2004;114(4):495–503.

    PubMed  CAS  Google Scholar 

  40. Beckman JA, Goldfine AB, Gordon MB, Garrett LA, Creager MA. Inhibition of protein kinase Cbeta prevents impaired endothelium-dependent vasodilation caused by hyperglycemia in humans. Circ Res. 2002;90(1):107–11.

    Article  PubMed  CAS  Google Scholar 

  41. Francia P, delli Gatti C, Bachschmid M, et al. Deletion of p66shc gene protects against age-related endothelial dysfunction. Circulation. 2004;110(18):2889–95.

    Article  PubMed  CAS  Google Scholar 

  42. Yamamori T, White AR, Mattagajasingh I, et al. P66shc regulates endothelial NO production and endothelium-dependent vasorelaxation: implications for age-associated vascular dysfunction. J Mol Cell Cardiol. 2005;39(6):992–5.

    Article  PubMed  CAS  Google Scholar 

  43. Pinton P, Rimessi A, Marchi S, et al. Protein kinase C beta and prolyl isomerase 1 regulate mitochondrial effects of the life-span determinant p66Shc. Science. 2007;315(5812):659–63.

    Article  PubMed  CAS  Google Scholar 

  44. Giorgio M, Migliaccio E, Orsini F, et al. Electron transfer between cytochrome c and p66Shc generates reactive oxygen species that trigger mitochondrial apoptosis. Cell. 2005;122(2):221–33.

    Article  PubMed  CAS  Google Scholar 

  45. Doughan AK, Harrison DG, Dikalov SI. Molecular mechanisms of angiotensin II-mediated mitochondrial dysfunction: linking mitochondrial oxidative damage and vascular endothelial dysfunction. Circ Res. 2008;102(4):488–96.

    Article  PubMed  CAS  Google Scholar 

  46. Davis B, Zou MH. CD40 ligand-dependent tyrosine nitration of prostacyclin synthase in vivo. Circulation. 2005;112(14): 2184–92.

    Article  PubMed  CAS  Google Scholar 

  47. Davidson SM, Duchen MR. Effects of NO on mitochondrial function in cardiomyocytes: Pathophysiological relevance. Cardiovasc Res. 2006;71(1):10–21.

    Article  PubMed  CAS  Google Scholar 

  48. Jornot L, Maechler P, Wollheim CB, Junod AF. Reactive oxygen metabolites increase mitochondrial calcium in endothelial cells: implication of the Ca2+/Na+ exchanger. J Cell Sci. 1999;112(Pt 7):1013–22.

    PubMed  CAS  Google Scholar 

  49. Ballinger SW, Patterson C, Yan CN, et al. Hydrogen peroxide- and peroxynitrite-induced mitochondrial DNA damage and dysfunction in vascular endothelial and smooth muscle cells. Circ Res. 2000;86(9):960–6.

    Article  PubMed  CAS  Google Scholar 

  50. Nishikawa T, Edelstein D, Du XL, et al. Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature. 2000;404(6779):787–90.

    Article  PubMed  CAS  Google Scholar 

  51. Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature. 2001;414(6865):813–20.

    Article  PubMed  CAS  Google Scholar 

  52. Du X, Matsumura T, Edelstein D, et al. Inhibition of GAPDH activity by poly(ADP-ribose) polymerase activates three major pathways of hyperglycemic damage in endothelial cells. J Clin Invest. 2003;112(7):1049–57.

    PubMed  CAS  Google Scholar 

  53. Reusch JE. Diabetes, microvascular complications, and cardiovascular complications: what is it about glucose? J Clin Invest. 2003;112(7):986–8.

    PubMed  CAS  Google Scholar 

  54. Du X, Edelstein D, Obici S, Higham N, Zou MH, Brownlee M. Insulin resistance reduces arterial prostacyclin synthase and eNOS activities by increasing endothelial fatty acid oxidation. J Clin Invest. 2006;116(4):1071–80.

    Article  PubMed  CAS  Google Scholar 

  55. Mabile L, Meilhac O, Escargueil-Blanc I, et al. Mitochondrial function is involved in LDL oxidation mediated by human cultured endothelial cells. Arterioscler Thromb Vasc Biol. 1997;17(8): 1575–82.

    Article  PubMed  CAS  Google Scholar 

  56. Schmidt AM, Hori O, Chen JX, et al. Advanced glycation endproducts interacting with their endothelial receptor induce expression of vascular cell adhesion molecule-1 (VCAM-1) in cultured human endothelial cells and in mice. A potential mechanism for the accelerated vasculopathy of diabetes. J Clin Invest. 1995;96(3): 1395–403.

    Article  PubMed  CAS  Google Scholar 

  57. Brodsky SV, Gao S, Li H, Goligorsky MS. Hyperglycemic switch from mitochondrial nitric oxide to superoxide production in endothelial cells. Am J Physiol Heart Circ Physiol. 2002;283(5):H2130–9.

    PubMed  CAS  Google Scholar 

  58. Dedkova EN, Ji X, Lipsius SL, Blatter LA. Mitochondrial calcium uptake stimulates nitric oxide production in mitochondria of bovine vascular endothelial cells. Am J Physiol Cell Physiol. 2004;286(2):C406–15.

    Article  PubMed  CAS  Google Scholar 

  59. Dedkova EN, Blatter LA. Modulation of mitochondrial Ca2+ by nitric oxide in cultured bovine vascular endothelial cells. Am J Physiol Cell Physiol. 2005;289(4):C836–45.

    Article  PubMed  CAS  Google Scholar 

  60. Ghafourifar P, Schenk U, Klein SD, Richter C. Mitochondrial nitric-oxide synthase stimulation causes cytochrome c release from isolated mitochondria. Evidence for intramitochondrial peroxynitrite formation. J Biol Chem. 1999;274(44):31185–8.

    Article  PubMed  CAS  Google Scholar 

  61. Detaille D, Guigas B, Chauvin C, et al. Metformin prevents high-glucose-induced endothelial cell death through a mitochondrial permeability transition-dependent process. Diabetes. 2005;54(7): 2179–87.

    Article  PubMed  CAS  Google Scholar 

  62. Recchioni R, Marcheselli F, Moroni F, Pieri C. Apoptosis in human aortic endothelial cells induced by hyperglycemic condition involves mitochondrial depolarization and is prevented by N-acetyl-L-cysteine. Metabolism. 2002;51(11):1384–8.

    Article  PubMed  CAS  Google Scholar 

  63. Don AS, Kisker O, Dilda P, et al. A peptide trivalent arsenical inhibits tumor angiogenesis by perturbing mitochondrial function in angiogenic endothelial cells. Cancer Cell. 2003;3(5):497–509.

    Article  PubMed  CAS  Google Scholar 

  64. Dimmeler S, Haendeler J, Galle J, Zeiher AM. Oxidized low-density lipoprotein induces apoptosis of human endothelial cells by activation of CPP32-like proteases. A mechanistic clue to the ‘response to injury’ hypothesis. Circulation. 1997;95(7):1760–3.

    Article  PubMed  CAS  Google Scholar 

  65. Choy JC, Granville DJ, Hunt DW, McManus BM. Endothelial cell apoptosis: biochemical characteristics and potential implications for atherosclerosis. J Mol Cell Cardiol. 2001;33(9):1673–90.

    Article  PubMed  CAS  Google Scholar 

  66. Chen J, Mehta JL, Haider N, Zhang X, Narula J, Li D. Role of caspases in Ox-LDL-induced apoptotic cascade in human coronary artery endothelial cells. Circ Res. 2004;94(3):370–6.

    Article  PubMed  CAS  Google Scholar 

  67. Matsunaga T, Iguchi K, Nakajima T, et al. Glycated high-density lipoprotein induces apoptosis of endothelial cells via a mitochondrial dysfunction. Biochem Biophys Res Commun. 2001;287(3): 714–20.

    Article  PubMed  CAS  Google Scholar 

  68. Walter DH, Haendeler J, Galle J, Zeiher AM, Dimmeler S. Cyclosporin A inhibits apoptosis of human endothelial cells by preventing release of cytochrome C from mitochondria. Circulation. 1998;98(12):1153–7.

    Article  PubMed  CAS  Google Scholar 

  69. Vindis C, Elbaz M, Escargueil-Blanc I, et al. Two distinct calcium-dependent mitochondrial pathways are involved in oxidized LDL-induced apoptosis. Arterioscler Thromb Vasc Biol. 2005;25(3): 639–45.

    Article  PubMed  CAS  Google Scholar 

  70. Kumar S, Kostin S, Flacke JP, Reusch HP, Ladilov Y. Soluble adenylyl cyclase controls mitochondria-dependent apoptosis in coronary endothelial cells. J Biol Chem. 2009;284(22):14760–8.

    Article  PubMed  CAS  Google Scholar 

  71. Lee YH, Mungunsukh O, Tutino RL, Marquez AP, Day RM. Angiotensin-II-induced apoptosis requires regulation of nucleolin and Bcl-xL by SHP-2 in primary lung endothelial cells. J Cell Sci. 2010;123(Pt 10):1634–43.

    Article  PubMed  CAS  Google Scholar 

  72. Stoneman VE, Bennett MR. Role of apoptosis in atherosclerosis and its therapeutic implications. Clin Sci (Lond). 2004;107(4): 343–54.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. The Molecular Cardiology and Neuromuscular Institute, Highland Park, NJ, USA

    José Marín-García M.D.

Authors
  1. José Marín-García M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer Science+Business Media New York

About this chapter

Cite this chapter

Marín-García, J. (2013). Endothelial Mitochondria: Contribution to Cardiovascular Function and Disease. In: Mitochondria and Their Role in Cardiovascular Disease. Springer, Boston, MA. https://doi.org/10.1007/978-1-4614-4599-9_7

Download citation

  • DOI: https://doi.org/10.1007/978-1-4614-4599-9_7

  • Published:

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4614-4598-2

  • Online ISBN: 978-1-4614-4599-9

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation