Skip to main content
SpringerLink
Log in

Crystals in Atherosclerosis: Crystal Cholesterol Structures, Morphologies, Formation and Dissolution. What Do We Know?

  • Chapter
  • First Online:
Cholesterol Crystals in Atherosclerosis and Other Related Diseases

Part of the book series: Contemporary Cardiology ((CONCARD))

  • 197 Accesses

Abstract

We start with a bird’s eye view of the shapes, sizes, locations, and of the components of the close environment of cholesterol crystals in the diseased tissue, listing the questions that these observations raise. We address these questions by first examining cholesterol crystal structures and polymorphism, and then describing the fundamental processes that control crystal morphology, crystal nucleation, and crystal dissolution and their manifestation in atherosclerotic lesions. In each section, we compare the observations made in the diseased tissues to the evidence collected in related pathological conditions and in model systems involving cholesterol crystals, and the processing thereof. Finally, we derive the possible manifestations and consequences of these processes in the formation and fate of atherosclerotic plaques.

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 119.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 159.99
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

Similar content being viewed by others

References

  1. Small DM. George Lyman Duff memorial lecture. Progression and regression of atherosclerotic lesions. Insights from lipid physical biochemistry. Arteriosclerosis. 1988;8:103–29.

    Article  CAS  PubMed  Google Scholar 

  2. Duewell P, Kono H, Rayner KJ, Sirois CM, Vladimer G, Bauernfeind FG, Abela GS, Franchi L, Nunez G, Schnurr M, Espevik T, Lien E, Fitzgerald KA, Rock KL, Moore KJ, Wright SD, Hornung V, Latz E. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature. 2010;464:1357–61.

    Google Scholar 

  3. Chistiakov DA, Bobryshev YV, Orekhov AN. Macrophage-mediated cholesterol handling in atherosclerosis. J Cell Mol Med. 2016;20:17–28.

    Article  CAS  PubMed  Google Scholar 

  4. Katz S, Shipley GG, Small D. Physical chemistry of the lipids of human atherosclerotic lesions. Demonstration of a lesion intermediate between fatty streaks and advanced plaques. J Clin Investig. 1976;58:200–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Small DM, Shipley GG. Physical-chemical basis of Lipid deposition in atherosclerosis: the physical state of the lipids helps to explain lipid deposition and lesion reversal in atherosclerosis. Science. 1974;185:222–9.

    Article  CAS  PubMed  Google Scholar 

  6. Capua-Shenkar J, Varsano N, Itzhak N-R, Kaplan-Ashiri I, Rechav K, Jin X, Niimi M, Fan J, Kruth HS, Addadi L. Examining atherosclerotic lesions in three dimensions at the nanometer scale with cryo-FIB-SEM. Proc Natl Acad Sci U S A. 2022;119:e2205475119.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Lehti S, Nguyen SD, Belevich I, Vihinen H, Heikkilä HM, Soliymani R, Käkelä R, Saksi J, Jauhiainen M, Grabowski GA. Extracellular lipids accumulate in human carotid arteries as distinct three-dimensional structures and have proinflammatory properties. Am J Clin Pathol. 2018;188:525–38.

    Article  CAS  Google Scholar 

  8. Varsano N, Beghi F, Elad N, Pereiro E, Dadosh T, Pinkas I, Perez-Berna AJ, Jin X, Kruth HS, Leiserowitz L, Addadi L. Two polymorphic cholesterol monohydrate crystal structures form in macrophage culture models of atherosclerosis. Proc Natl Acad Sci U S A. 2018;115:7662–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Tangirala RK, Jerome WG, Jones N, Small DM, Johnson W, Glick J, Mahlberg F, Rothblat G. Formation of cholesterol monohydrate crystals in macrophage-derived foam cells. J Lipid Res. 1994;35:93–104.

    Article  CAS  PubMed  Google Scholar 

  10. Shio H, Haley N, Fowler S. Characterization of lipid-laden aortic cells from cholesterol-fed rabbits. III. Intracellular localization of cholesterol and cholesteryl ester. Lab Invest. 1979;41:160–7.

    CAS  PubMed  Google Scholar 

  11. Kruth HS. Macrophage foam cells and atherosclerosis. Front Biosci. 2001;6:D429–55.

    Article  CAS  PubMed  Google Scholar 

  12. Vidavsky N, Akiva A, Kaplan-Ashiri I, Rechav K, Addadi L, Weiner S, Schertel A. Cryo-FIB-SEM serial milling and block face imaging: large volume structural analysis of biological tissues preserved close to their native state. J Struct Biol. 2016;196:487–95.

    Article  CAS  PubMed  Google Scholar 

  13. Mahamid J, Tegunov D, Maiser A, Arnold J, Leonhardt H, Plitzko JM, Baumeister W. Liquid-crystalline phase transitions in lipid droplets are related to cellular states and specific organelle association. Proc Natl Acad Sci U S A. 2019;116:16866–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Spehner D, Steyer AM, Bertinetti L, Orlov I, Benoit L, Pernet-Gallay K, Schertel A, Schultz P. Cryo-FIB-SEM as a promising tool for localizing proteins in 3D. J Struct Biol. 2020;211:107528.

    Article  CAS  PubMed  Google Scholar 

  15. Bocan T, Schifani T, Guyton J. Ultrastructural examination of the human aortic fibrolipid lesion-formation of the atherosclerotic lipid-rich core. Am J Clin Pathol. 1985;123:413–24.

    Google Scholar 

  16. Fry L, Lee A, Khan S, Aziz K, Vedre A, Abela GS. Effect of aspirin on cholesterol crystallization: a potential mechanism for plaque stabilization. Am Heart J. 2022;13:100083.

    Google Scholar 

  17. Kruth HS. Cholesterol deposition in atherosclerotic lesions. Cholesterol. 1997;28:319–62.

    CAS  Google Scholar 

  18. Saad HY, Higuchi WI. Water solubility of cholesterol. J Pharm Sci. 1965;54:1205–6.

    Article  CAS  PubMed  Google Scholar 

  19. Haberland ME, Reynolds JA. Self-association of cholesterol in aqueous solution. Proc Natl Acad Sci U S A. 1973;70:2313–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Sackmann E. Biological membranes architecture and function. Amsterdam: Elsevier Science B.V; 1995.

    Book  Google Scholar 

  21. Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P. Molecular biology of the cell. Scand J Rheumatol. 2003;32:125.

    Google Scholar 

  22. Smondyrev AM, Berkowitz ML. Structure of dipalmitoylphosphatidylcholine/cholesterol bilayer at low and high cholesterol concentrations: molecular dynamics simulation. Biophys J. 1999;77:2075–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Berg J, Tymoczko J, Stryer L. Biochemistry: international version. New York: W. H. Freeman; 2002.

    Google Scholar 

  24. Ziblat R, Leiserowitz L, Addadi L. Crystalline domain structure and cholesterol crystal nucleation in single hydrated DPPC: cholesterol: POPC bilayers. J Am Chem Soc. 2010;132:9920–7.

    Article  CAS  PubMed  Google Scholar 

  25. Ziblat R, Kjaer K, Leiserowitz L, Addadi L. Structure of cholesterol/lipid ordered domains in monolayers and single hydrated bilayers. Angew Chem Int Ed. 2009;48:8958–61.

    Article  CAS  Google Scholar 

  26. Ziblat R, Fargion I, Leiserowitz L, Addadi L. Spontaneous formation of two-dimensional and three-dimensional cholesterol crystals in single hydrated lipid bilayers. Biophys J. 2012;103:255–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Craven BM. Crystal structure of cholesterol monohydrate. Nature. 1976;260:727–9.

    Article  CAS  PubMed  Google Scholar 

  28. Solomonov I, Weygand MJ, Kjaer K, Rapaport H, Leiserowitz L. Trapping crystal nucleation of cholesterol monohydrate: relevance to pathological crystallization. Biophys J. 2005;88:1809–17.

    Article  CAS  PubMed  Google Scholar 

  29. Shepelenko M, Hirsch A, Varsano N, Beghi F, Addadi L, Kronik L, Leiserowitz L. Polymorphism, structure, and nucleation of cholesterol· H2O at aqueous interfaces and in pathological media: revisited from a computational perspective. J Am Chem Soc. 2021;144:5304–14.

    Article  Google Scholar 

  30. Konikoff F, Chung DS, Donovan J, Small D, Carey M. Filamentous, helical, and tubular microstructures during cholesterol crystallization from bile. Evidence that cholesterol does not nucleate classic monohydrate plates. J Clin Investig. 1992;90:1155–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Weihs D, Schmidt J, Goldiner I, Danino D, Rubin M, Talmon Y, Konikoff FM. Biliary cholesterol crystallization characterized by single-crystal cryogenic electron diffraction. J Lipid Res. 2005;46:942–8.

    Article  CAS  PubMed  Google Scholar 

  32. Varsano N, Capua-Shenkar J, Leiserowitz L, Addadi L. Crystalline cholesterol: the material and its assembly lines. Annu Rev Mat Res. 2022;52:52.

    Article  Google Scholar 

  33. Wells A. XXV. Crystal habit and internal structure.—II. Lond Edinb Dublin Philos Mag. 1946;37:217–36.

    Article  CAS  Google Scholar 

  34. Hartman P, Perdok W. On the relations between structure and morphology of crystals. I. Acta Crystallogr. 1955;8:49–52.

    Article  CAS  Google Scholar 

  35. Weissbuch I, Addadi L, Lahav M, Leiserowitz L. Molecular recognition at crystal interfaces. Science. 1991;253:637–45.

    Article  CAS  PubMed  Google Scholar 

  36. Burton W, Cabrera N, Frank F. Role of dislocations in crystal growth. Nature. 1949;163:398–9.

    Article  CAS  Google Scholar 

  37. Kellner-Weibel G, Yancey P, Jerome W, Walser T, Mason R, Phillips M, Rothblat G. Crystallization of free cholesterol in model macrophage foam cells. Arterioscler Thromb Vasc Biol. 1999;19:1891–8.

    Article  CAS  PubMed  Google Scholar 

  38. Chung DS, Benedek GB, Konikoff FM, Donovan JM. Elastic free energy of anisotropic helical ribbons as metastable intermediates in the crystallization of cholesterol. Proc Natl Acad Sci U S A. 1993;90:11341–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Varsano N, Beghi F, Dadosh T, Elad N, Pereiro E, Haran G, Leiserowitz L, Addadi L. The effect of the phospholipid bilayer environment on cholesterol crystal polymorphism. ChemPlusChem. 2019;84:338–44.

    Article  CAS  PubMed  Google Scholar 

  40. Khaykovich B, Kozlova N, Choi W, Lomakin A, Hossain C, Sung Y, Dasari RR, Feld MS, Benedek GB. Thickness–radius relationship and spring constants of cholesterol helical ribbons. Proc Natl Acad Sci U S A. 2009;106:15663–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Ostwald W. Über die vermeintliche Isomerie des roten und gelben Quecksilberoxyds und die Oberflächenspannung fester Körper. Z Phys Chem. 1900;34:495–503.

    Article  Google Scholar 

  42. Ratke L, Voorhees PW. Growth and coarsening: Ostwald ripening in material processing. Berlin: Springer Science & Business Media; 2002.

    Book  Google Scholar 

  43. Frank FC. The influence of dislocations on crystal growth. Discuss Faraday Soc. 1949;5:48–54.

    Article  Google Scholar 

  44. Walton AG. Nucleation of crystals from solution: mechanisms of precipitation are fundamental to analytical and physiological processes. Science. 1965;148:601–7.

    Article  CAS  PubMed  Google Scholar 

  45. Ziblat R, Leiserowitz L, Addadi L. Crystalline Lipid domains: characterization by X-ray diffraction and their relation to biology. Angew Chem Int Ed. 2011;50:3620–9.

    Article  CAS  Google Scholar 

  46. Varsano N, Dadosh T, Kapishnikov S, Pereiro E, Shimoni E, Jin X, Kruth HS, Leiserowitz L, Addadi L. Development of correlative cryo-soft X-ray tomography and stochastic reconstruction microscopy. A study of cholesterol crystal early formation in cells. J Am Chem Soc. 2016;138:14931–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Tauchi-Sato K, Ozeki S, Houjou T, Taguchi R, Fujimoto T. The surface of lipid droplets is a phospholipid monolayer with a unique fatty acid composition. J Biol Chem. 2002;277:44507–12.

    Article  CAS  PubMed  Google Scholar 

  48. Guyton JR, Klemp KF. The lipid-rich core region of human atherosclerotic fibrous plaques. Prevalence of small lipid droplets and vesicles by electron microscopy. Am J Clin Pathol. 1989;134:705.

    CAS  Google Scholar 

  49. Dove PM, Han N, De Yoreo JJ. Mechanisms of classical crystal growth theory explain quartz and silicate dissolution behavior. Proc Natl Acad Sci U S A. 2005;102:15357–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Park S, Sut TN, Ma GJ, Parikh AN, Cho N-J. Crystallization of cholesterol in phospholipid membranes follows Ostwald’s rule of stages. J Am Chem Soc. 2020;142:21872–82.

    Article  CAS  PubMed  Google Scholar 

  51. Small DM, Bond MG, Waugh D, Prack M, Sawyer J. Physicochemical and histological changes in the arterial wall of nonhuman primates during progression and regression of atherosclerosis. J Clin Investig. 1984;73:1590–605.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Feig J. Regression of atherosclerosis: insights from animal and clinical studies. Ann Glob Health. 2014;80:13–23.

    Article  PubMed  Google Scholar 

  53. Brown B, Zhao X, Sacco D, Albers J, Lipid lowering and plaque regression. New insights into prevention of plaque disruption and clinical events in coronary disease. Circulation. 1993;87:1781–91.

    Article  CAS  PubMed  Google Scholar 

  54. Flynn G, Shah Y, Prakongpan S, Kwan K, Higuchi W, Hofmann A. Cholesterol solubility in organic solvents. J Pharm Sci. 1979;68:1090–7.

    Article  CAS  PubMed  Google Scholar 

  55. Abendan RS, Swift JA, design. Dissolution on cholesterol monohydrate single-crystal surfaces monitored by in situ atomic force microscopy. J Cryst Growth. 2005;5:2146–53.

    Article  CAS  Google Scholar 

  56. Nasiri M, Janoudi A, Vanderberg A, Frame M, Flegler C, Flegler S, Abela GS, Technique. Role of cholesterol crystals in atherosclerosis is unmasked by altering tissue preparation methods. Microsc Res Tech. 2015;78:969–74.

    Article  CAS  PubMed  Google Scholar 

  57. Abela GS, Vedre A, Janoudi A, Huang R, Durga S, Tamhane U. Effect of statins on cholesterol crystallization and atherosclerotic plaque stabilization. Am J Cardiol. 2011;107:1710–7.

    Article  CAS  PubMed  Google Scholar 

  58. Zimmerman HE. Molecular mechanism of cell-substrate recognition and attachment. Feinberg Graduate School, Ph.D. Thesis; 2001.

    Google Scholar 

  59. Zimmerman E, Geiger B, Addadi L. Initial stages of cell-matrix adhesion can be mediated and modulated by cell-surface hyaluronan. Biophys J. 2002;82:1848–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Adams C, Abdulla Y. The action of human high density lipoprotein on cholesterol crystals. Part 1. Light-microscopic observations. Atherosclerosis. 1978;31:465–71.

    Article  CAS  PubMed  Google Scholar 

  61. Abdulla Y, Adams C. The action of human high density lipoprotein on cholesterol crystals. Part 2. Biochemical observations. Atherosclerosis. 1978;31:473–80.

    Article  CAS  PubMed  Google Scholar 

  62. Luo Y, Guo Y, Wang H, Yu M, Hong K, Li D, Li R, Wen B, Hu D, Chang L, Sun D, Shchwendeman SA, Chen YE. Phospholipid nanoparticles: therapeutic potentials against atherosclerosis via reducing cholesterol crystals and inhibiting inflammation. EBioMedicine. 2021;74:103725.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Niyonzima N, Samstad EO, Aune MH, Ryan L, Bakke SS, Rokstad AM, Wright SD, Damås JK, Mollnes TE, Latz E, Espevik T. Reconstituted high-density lipoprotein attenuates cholesterol crystal–induced inflammatory responses by reducing complement activation. J Immunol. 2015;195:257–64.

    Google Scholar 

  64. Thacker SG, Zarzour A, Chen Y, Alcicek MS, Freeman LA, Sviridov DO, Demosky SJ Jr, Remaley ATx. High-density lipoprotein reduces inflammation from cholesterol crystals by inhibiting inflammasome activation. Immunology. 2016;149:306–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. McConathy WJ, Koren E, Stiers DL. Cholesterol crystal uptake and metabolism by P388D1 macrophages. Atherosclerosis. 1989;77:221–5.

    Article  CAS  PubMed  Google Scholar 

  66. Kruth HS, Skarlatos SI, Lilly K, Chang J, Ifrim I. Sequestration of acetylated LDL and cholesterol crystals by human monocyte-derived macrophages. J Cell Biol. 1995;129:133–45.

    Article  CAS  PubMed  Google Scholar 

  67. Kruth HS, Skarlatos SI, Gaynor PM, Gamble W. Production of cholesterol-enriched nascent high density lipoproteins by human monocyte-derived macrophages is a mechanism that contributes to macrophage cholesterol efflux. J Biol Chem. 1994;269:24511–8.

    Article  CAS  PubMed  Google Scholar 

  68. Zhang W-Y, Gaynor PM, Kruth HS. Apolipoprotein E produced by human monocyte-derived macrophages mediates cholesterol efflux that occurs in the absence of added cholesterol acceptors. J Biol Chem. 1996;271:28641–6.

    Article  CAS  PubMed  Google Scholar 

  69. Jin X, Dimitriadis EK, Liu Y, Combs CA, Chang J, Varsano N, Stempinski E, Flores R, Jackson SN, Muller L, Woods AS, Addadi L, Kruth HS. Macrophages shed excess cholesterol in unique extracellular structures containing cholesterol microdomains. Arterioscler Thromb Vasc Biol. 2018;38:1504–18.

    Google Scholar 

  70. Abela GS, Kalavakunta JK, Janoudi A, Leffler D, Dhar G, Salehi N, Cohn J, Shah I, Karve M, Kotaru VPK, Gupta V, David S, Narisetty KK, Rich M, Vanderberg A, Pathak DR, Shamoun FE. Frequency of cholesterol crystals in culprit coronary artery aspirate during acute myocardial infarction and their relation to inflammation and myocardial injury. Am J Cardiol. 2017;120:1699–707.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Chemical and Structural Biology, Weizmann Institute of Science, Rehovot, Israel

    Jenny Capua-Shenkar & Lia Addadi

  2. Department of Chemical Research Support, Weizmann Institute of Science, Rehovot, Israel

    Neta Varsano

  3. Experimental Atherosclerosis Section, National Institutes of Health, Bethesda, MD, USA

    Howard Kruth

Authors
  1. Jenny Capua-Shenkar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Neta Varsano
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Howard Kruth
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lia Addadi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lia Addadi .

Editor information

Editors and Affiliations

  1. Department of Medicine, Division of Cardiovascular Medicine, Michigan State University, East Lansing, MI, USA

    George S. Abela

  2. The Heart and Vascular Research Institute, Sir Charles Gairdner Hospital, Perth, WA, Australia

    Stefan Mark Nidorf

Rights and permissions

Reprints and permissions

Copyright information

© 2023 The Author(s), under exclusive license to Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Capua-Shenkar, J., Varsano, N., Kruth, H., Addadi, L. (2023). Crystals in Atherosclerosis: Crystal Cholesterol Structures, Morphologies, Formation and Dissolution. What Do We Know?. In: Abela, G.S., Nidorf, S.M. (eds) Cholesterol Crystals in Atherosclerosis and Other Related Diseases. Contemporary Cardiology. Humana, Cham. https://doi.org/10.1007/978-3-031-41192-2_4

Download citation

  • DOI: https://doi.org/10.1007/978-3-031-41192-2_4

  • Published:

  • Publisher Name: Humana, Cham

  • Print ISBN: 978-3-031-41191-5

  • Online ISBN: 978-3-031-41192-2

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation