Biologic Nanoparticles and Vascular Disease

  • Maria K. Schwartz
  • John C. Lieske
  • Virginia M. MillerEmail author


Sustained or repeating chronic infections have been linked to arterial calcification. Biologic nanoparticles (NPs) that propagate in culture have been isolated from calcified soft tissues. When inoculated into experimental animals, NPs appear to exacerbate the arterial response to injury, up to and including medial discontinuity and vascular occlusion. These NPs may be re-assembled proteins and microvesicles derived from mammalian cells and/or microorganisms.


Arterial calcification Calcium Hydroxyapatite Infection Inflammation 


  1. 1.
    Abedin M, Tintut Y, Demer LL. (2004) Vascular calcification: mechanisms and clinical ramifications. Arterioscler Thromb Vasc Biol 24:1161–1170.CrossRefPubMedGoogle Scholar
  2. 2.
    Agababov RM, Abashina TN, Suzina NE, et al. (2007) Link between the early calcium deposition in placenta and nanobacterial-like infection. J Biosci 32:1163–1168.CrossRefPubMedGoogle Scholar
  3. 3.
    Aikawa E, Nahrendorf M, Figueiredo JL, et al. (2007) Osteogenesis associates with inflammation in early-stage atherosclerosis evaluated by molecular imaging in vivo. Circulation 116:2841–2850.CrossRefPubMedGoogle Scholar
  4. 4.
    Akerman KK, Juronen I, Kajander EO. (1993) Scanning electron microscopy of nanobacteria – novel biofilm producing organisms in blood. Scan Electron Microsc 15:sIII:90–91.Google Scholar
  5. 5.
    Akerman KK, Kuikka JT, Ciftcioglu N, et al. (1997) Radiolabeling and in vivo distribution of nanobacteria in rabbit. Proc SPIE 3111:436–442.CrossRefGoogle Scholar
  6. 6.
    Arbour NC, Lorenz E, Schutte BC, et al. (2000) TLR4 mutations are associated with endotoxin hyporesponsiveness in humans. Nat Genet 25:187–191.CrossRefPubMedGoogle Scholar
  7. 7.
    Beck JD, Offenbacher S. (2001) The association between periodontal diseases and cardiovascular diseases: A state-of-the-science review. Ann Periodontol 6:9–15.CrossRefPubMedGoogle Scholar
  8. 8.
    Boskey AL, Boyan BD, Schwartz Z. (1997) Matrix vesicles promote mineralization in a gelatin gel. Calcif Tissue Int 60:309–315.CrossRefPubMedGoogle Scholar
  9. 9.
    Bratos-Perez MA, Sanchez PL, Garcia de Cruz S, et al. (2008) Association between self-replicating calcifying nanoparticles and aortic stenosis: A possible link to valve calcification. Eur Heart J 29:371–376.CrossRefPubMedGoogle Scholar
  10. 10.
    Ciftcioglu N, Bjorklund M, Kuorikoski K, et al. (1999) Nanobacteria: An infectious cause for kidney stone formation. Kidney Int 56:1893–1898.CrossRefPubMedGoogle Scholar
  11. 11.
    Ciftcioglu N, Haddad RW, Golden CD, et al. (2005) A potential cause for kidney stone formation during space flights: Enhanced growth of nanobacteria in microgravity. Kidney Int 67:483–491.CrossRefPubMedGoogle Scholar
  12. 12.
    Ciftcioglu N, Kajander EO. (1998) Interaction of nanobacteria with cultured mammalian cells. Pathophysiology 4:259–270.CrossRefGoogle Scholar
  13. 13.
    Ciftcioglu N, Miller-Hjelle MA, Hjelle JT, et al. (2002) Inhibition of nanobacteria by antimicrobial drugs as measured by a modified microdilution method. Antimicrob Agents Chemother 46:2077–2086.CrossRefPubMedGoogle Scholar
  14. 14.
    Cisar JO, Xu D-Q, Thompson J, et al. (2000) An alternative interpretation of nanobacteria-induced biomineralization. Proc Natl Acad Sci USA. 97:11511–11515.CrossRefPubMedGoogle Scholar
  15. 15.
    Costerton JW, Stewart PS, Greenberg EP. (1999) Bacterial biofilms: a common cause of persistent infections. Science 284:1318–1322.CrossRefPubMedGoogle Scholar
  16. 16.
    Detrano R, Guerci AD, Carr JJ, et al. (2008) Coronary calcium as a predictor of coronary events in four racial or ethnic groups. N Engl J Med 358:1336–1345.CrossRefPubMedGoogle Scholar
  17. 17.
    Diamant M, Tushuizen ME, Sturk A, et al. (2004) Cellular microparticles: new players in the field of vascular disease? Eur J Clin Invest 34:392–401.CrossRefPubMedGoogle Scholar
  18. 18.
    Doherty TM, Asotra K, Fitzpatrick LA, et al. (2003) Calcification in atherosclerosis: Bone biology and chronic inflammation at the arterial crossroads. Proc Natl Acad Sci USA 100:11201–11206.CrossRefPubMedGoogle Scholar
  19. 19.
    Epstein SE, Zhu J, Burnett MS, et al. (2000) Infection and atherosclerosis: Potential roles of pathogen burden and molecular mimicry. Arterioscler Thromb Vasc Biol 20:1417–1420.PubMedGoogle Scholar
  20. 20.
    Folk RL. (1992) Bacteria and nannobacteria revealed in hardgrounds, calcite cements, native sulfur, sulfide minerals, and travertines. Geological Society of America Annual Meeting, Abstracts with Programs 24:104Google Scholar
  21. 21.
    Folk RL. (1998) Nannobacteria in the natural environment and in medicine. Alpe Adria Microbiol J 7:87–95.Google Scholar
  22. 22.
    Greenhill NS, Presland MR, Rogers KM, et al. (1985) X-ray microanalysis of mineralized matrix vesicles of experimental saccular aneurysms. Exp Mol Pathol 43:220–232.CrossRefPubMedGoogle Scholar
  23. 23.
    Hecht HS, Budoff MJ, Berman DS, et al. (2006) Coronary artery calcium scanning: Clinical paradigms for cardiac risk assessment and treatment. Am Heart J 151:1139–1146.CrossRefPubMedGoogle Scholar
  24. 24.
    Hill AB. (1965) The environment and disease: association or causation? Proc R Soc Med 58:295–300.PubMedGoogle Scholar
  25. 25.
    Hjelle JT, Miller-Hjelle MA, Poxton IR, et al. (2000) Endotoxin and nanobacteria in polycystic kidney disease. Kidney Int 57:2360–2374.CrossRefPubMedGoogle Scholar
  26. 26.
    Huber H, Hohn MJ, Rachel R, et al. (2002) A new phylum of Archaea represented by a nanosized hyperthermophilic symbiont. Nature 417:63–67.CrossRefPubMedGoogle Scholar
  27. 27.
    Jayachandran M, Litwiller RD, Owen WG, et al. (2009 ) Circulating microparticles and endogenous estrogen in newly menopausal women. Climacteric 12:1–8.CrossRefGoogle Scholar
  28. 28.
    Jayachandran M, Miller VM, Owen WG. (2008) Blood borne microparticles of age-associated thrombogenicity. Basic Clin Pharmacol Toxicol 102:56.Google Scholar
  29. 29.
    Kajander EO, Ciftcioglu N. (1998) Nanobacteria: An alternative mechanism for pathogenic intra- and extracellular calcification and stone formation. Proc Natl Acad Sci USA 95:8274–8279.CrossRefPubMedGoogle Scholar
  30. 30.
    Kajander EO, Kuronen I, Akerman KK, et al. (1997) Nanobacteria from blood, the smallest culturable autonomously replicating agent on Earth. Proc SPIE 3111:420–428.CrossRefGoogle Scholar
  31. 31.
    Khullar M, Sharma SK, Singh SK, et al. (2004) Morphological and immunological characteristics of nanobacteria from human renal stones of a north Indian population. Urol Res 32:190–195.CrossRefPubMedGoogle Scholar
  32. 32.
    Kim KM. (1976) Calcification of matrix vesicles in human aortic valve and aortic media. Federation Proc 35:156–162.Google Scholar
  33. 33.
    Knoll A. (1999) Overview size limits of very small microorganisms: Proceedings of a Workshop. National Academy of Sciences, pp. 164.Google Scholar
  34. 34.
    Kockx MM, Muhring J, Bortier H, et al. (1996) Biotin- or digoxigenin-conjugated nucleotides bind to matrix vesicles in atherosclerotic plaques. Am J Pathol 148:1771–1777.PubMedGoogle Scholar
  35. 35.
    Kumar V, Farell G, Yu S, et al. (2006) Cell biology of pathologic renal calcification: contribution of crystal transcytosis, cell-mediated calcification, and nanoparticles. J Investig Med 54:412–424.CrossRefPubMedGoogle Scholar
  36. 36.
    Lakoski SG, Greenland P, Wong ND, et al. (2007) Coronary artery calcium scores and risk for cardiovascular events in women classified as “low risk” based on framingham risk score: the multi-ethnic study of atherosclerosis (MESA). Arch Intern Med 167:2437–2442.CrossRefPubMedGoogle Scholar
  37. 37.
    Libby P. (2002) Inflammation in atherosclerosis. Nature 420:868–874.CrossRefPubMedGoogle Scholar
  38. 38.
    Lynch SF, Ludlam CA. (2007) Plasma microparticles and vascular disorders. Br J Haematol 137:36–48.PubMedGoogle Scholar
  39. 39.
    Maniloff J. (1997) Nannobacteria: Size limits and evidence (letter; comment). Science 276:1776; discussion 1777.CrossRefPubMedGoogle Scholar
  40. 40.
    Manson J, Allison M, Rossouw JE, et al. (2007) Estrogen therapy and coronary-artery calcification. N Engl J Med 356:2591–2602.CrossRefPubMedGoogle Scholar
  41. 41.
    Martel J, Ding-E Young J. (2008) Purported nanobacteria in human blood as calcium carbonate nanoparticles. Proc Natl Acad Sci USA 105:5549–5554.CrossRefPubMedGoogle Scholar
  42. 42.
    Mathew G, McKay DS, Ciftcioglu N. (2008) Do blood-borne calcifying nanoparticles self-propagate? Int J Nanomedicine 3:265–275.PubMedGoogle Scholar
  43. 43.
    McKay DS, Gibson EK, Jr., Thomas-Keprta KL, et al. (1996) Search for past life on Mars: Possible relic biogenic activity in Martian meteorite ALH84001. Science 273:924–930.CrossRefPubMedGoogle Scholar
  44. 44.
    Miller VM, Black DM, Brinton EA, et al. (2009) Using basic science to design a clinical trial: Baseline Characteristics of Women Enrolled in the Kronos Early Estrogen Prevention Study (KEEPS). J Cardiovasc Transl Res 2:228–239.CrossRefPubMedGoogle Scholar
  45. 45.
    Miller VM, Hay M. (2004) Principles of sex-based differences in physiology: Advances in molecular and cell biology, vol. 34. London: Elsevier Publishing Company.Google Scholar
  46. 46.
    Miller VM, Rodgers G, Charlesworth JA, et al. (2004) Evidence of nanobacterial-like structures in human calcified arteries and cardiac valves. Am J Physiol Heart Circ Physiol 287:H1115–H1124.CrossRefPubMedGoogle Scholar
  47. 47.
    Muhlestein JB, Anderson JL. (2003) Chronic infection and coronary artery disease. Cardiol Clin 21:333–362.CrossRefPubMedGoogle Scholar
  48. 48.
    Nealson KH. (1997) Nannobacteria: Size limits and evidence. Science 276:1776; discussion 1777.PubMedGoogle Scholar
  49. 49.
    Nel A, Xia T, Madler L, et al. (2006) Toxic potential of materials at the nanolevel. Science 311:622–627.CrossRefPubMedGoogle Scholar
  50. 50.
    Prasad A, Zhu J, Halcox JPJ, et al. (2002) Predisposition to atherosclerosis by infections. Role of endothelial dysfunction. Circulation 106:184–190.CrossRefPubMedGoogle Scholar
  51. 51.
    Raoult D, Drancourt M, Azza S, et al. (2008) Nanobacteria are mineralo fetuin complexes. PLoS Pathog 4:e41.CrossRefPubMedGoogle Scholar
  52. 52.
    Rogers KM, Stehbens WE. (1986) The morphology of matrix vesicles produced in experimental arterial aneurysms of rabbits. Pathology 18:64–71.CrossRefPubMedGoogle Scholar
  53. 53.
    Ross R. (1986) The pathogenesis of atherosclerosis – an update. N Engl J Med 14:488–500.CrossRefGoogle Scholar
  54. 54.
    Schoppet M, Shanahan CM. (2008) Role for alkaline phosphatase as an inducer of vascular calcification in renal failure? Kidney Int 73:989–991.CrossRefPubMedGoogle Scholar
  55. 55.
    Schwartz MA-K, Lieske JC, Kumar V, et al. (2008) Human-derived nanoparticles and vascular responses to injury in rabbit carotid arteries: proof of principle. Int J Nanomedicine 3:243–248.PubMedGoogle Scholar
  56. 56.
    Schwartz MK, Hunter LW, Huebner M, et al. (2009) Characterization of biofilm formed by human-derived nanoparticles. Nanomedicine 4:931–941.CrossRefPubMedGoogle Scholar
  57. 57.
    Schwartz MK, Lieske JC, Hunter LW, et al. (2009) Systemic injection of planktonic forms of mammalian-derived nanoparticles alters arterial response to injury in rabbits. Am J Physiol Heart Circ Physiol 296:1434–1441.CrossRefGoogle Scholar
  58. 58.
    Sedivy R, Battistutti WB. (2003) Nanobacteria promote crystallization of psammoma bodies in ovarian cancer. APMIS 111:951–954.CrossRefPubMedGoogle Scholar
  59. 59.
    Shao JS, Cai J, Towler DA. (2006) Molecular mechanisms of vascular calcification: Lessons learned from the aorta. Arterioscler Thromb Vasc Biol 26:1423–1430.CrossRefPubMedGoogle Scholar
  60. 60.
    Shoskes DA, Thomas KD, Gomez E. (2005) Anti-nanobacterial therapy for men with chronic prostatitis/chronic pelvic pain syndrome and prostatic stones: Preliminary experience. J Urol 173:474–477.CrossRefPubMedGoogle Scholar
  61. 61.
    Sigrist M, Bungay P, Taal MW, et al. (2006) Vascular calcification and cardiovascular function in chronic kidney disease. Nephrol Dial Transplant 21:707–714.CrossRefPubMedGoogle Scholar
  62. 62.
    Vali H, McKee MD, Cifticioglu N, et al. (2001) Nanoforms: A new type of protein-associated mineralization. Geochim Cosmochim Acta 65:63–74.CrossRefGoogle Scholar
  63. 63.
    Wang L, Shen W, Wen J, et al. (2006) An animal model of black pigment gallstones caused by nanobacteria. Dig Dis Sci 51:1126–1132.CrossRefPubMedGoogle Scholar
  64. 64.
    Yang IA, Holloway JW, Ye S, et al. (2003) TLR4 Asp299Gly polymorphism is not associated with coronary artery stenosis. Atherosclerosis 170:187–190.CrossRefPubMedGoogle Scholar
  65. 65.
    Young JD, Martel J, Young D, et al. (2009) Characterization of granulations of calcium and apatite in serum as pleomorphic mineralo-protein complexes and as precursors of putative nanobacteria. PLoS One 4:e5421.CrossRefPubMedGoogle Scholar
  66. 66.
    Young JD, Martel J, Young L, et al. (2009) Putative nanobacteria represent physiological remnants and culture by-products of normal calcium homeostasis. PLoS One 4:e4417.CrossRefPubMedGoogle Scholar
  67. 67.
    Zhou Z, Hong L, Shen X, et al. (2008) Detection of nanobacteria infection in type III prostatitis. Urology 71:1091–1095.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Maria K. Schwartz
  • John C. Lieske
  • Virginia M. Miller
    • 1
    Email author
  1. 1.Departments of Surgery and Physiology and Biomedical EngineeringMayo ClinicRochesterUSA

Personalised recommendations