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The Role of Elastin Degradation in Vascular Calcification: Possibilities to Repair Elastin and Reverse Calcification

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Cardiovascular Calcification and Bone Mineralization

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

Abstract

Vascular calcification disrupts cardiovascular hemodynamics, and it is considered as a significant risk factor for all-cause mortality and morbidity. Elastin is an essential extracellular matrix component of the healthy arteries of nearly all vertebrates. The principle function of elastic fiber is to provide elasticity to the large blood vessels, allowing reversible deformation during cyclic hemodynamic loading without energy dissipation upon load retrieval. During aging and pathology-associated vascular diseases, elastic fiber degradation is an important predictor of disease progression. Elastin fragmentation and degradation and the resulting elastin-derived peptides cause the loss of arterial cellular homeostasis and ultimately vascular calcification. A large group of research studies is succeeded to halt or limit the calcification process. However, the treatment strategies that are focused on calcification reversal, subsequent elastin regeneration, and recapitulating the healthy arterial integrity are scarce. Moreover, almost all the treatments are based on either oral or systemic drug delivery that accompanies various side effects. To address these issues, authors have developed a nanoparticle-loaded targeting drug delivery approach that targets explicitly damaged elastic fibers in diseased arteries. This targeted therapy managed to reverse already developed vascular calcification in animal models first by calcium sequestration with ethylenediaminetetraacetic acid (EDTA) delivery, followed by elastic fiber regeneration via pentagalloyl glucose (PGG) delivery. Such therapies not only reversed calcification but decreased inflammation and enzyme activities while returning vascular smooth muscle cells to the healthy phenotype.

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Abbreviations

ACA:

Aortic calcification area

ACEi:

Angiotensin-converting enzyme inhibitors

AGE:

Advanced glycation end products

ALP:

Alkaline phosphatase

ARBs:

Angiotensin receptor blockers

B-GP or β-GP:

Beta-glycerophosphate

Ca:

Calcium

CAC:

Coronary artery calcium

CAD:

Coronary artery disease

CaSRs:

Calcium-sensing receptors

CCBs:

Calcium channel blockers

CKD:

Chronic kidney disease

DTPA:

Diethylenetriaminepentaacetic acid

ECM:

Extracellular matrix

EDPs:

Elastin-derived peptides

EDTA:

Ethylenediaminetetraacetic acid

ERC:

Elastin receptor complex

ESRD:

End-stage renal disease

FGF2:

Fibroblast growth factor 2

HA:

Hydroxyapatite

HAECs:

Human aortic endothelial cells

HASMCs:

Human aortic smooth muscle cells

huRANKL-KI:

Human RANKL knock in

IFNγ:

Interferon gamma

IL-1β:

Interleukin-1 beta

LAP:

Latency-associated peptides

LLC:

Large latent complex

LOX:

Lysyl oxidase

LRP6:

Low-density lipoprotein receptor-related protein 6

LTBP:

Latent TGF-β binding protein

LVH:

Left ventricular hypertrophy

MAC:

Medial arterial calcification

MAGP:

Microfibril-associated glycoprotein

MCRAs:

Mineralocorticoid receptor antagonists

MGP:

Matrix Gla protein

MMP:

Matrix metalloproteinase

MS:

Marfan’s syndrome

OPG:

Osteoprotegerin

P:

Phosphate

PGG:

Pentagalloyl glucose

Pi:

Inorganic phosphate

PLGA:

Poly(lactic-co-glycolic acid)

PPi:

Pyrophosphate

PTH:

Parathyroid hormone

PWV:

Pulse wave velocity

RAAS:

Renin-angiotensin-aldosterone system

RAGE:

Receptor for advanced glycation end products

sHPT:

Secondary hyperparathyroidism

SMCs:

Smooth muscle cells

SMαA:

Smooth muscle alpha actin

STS:

Sodium thiosulfate

TGF-b:

Transforming growth factor-beta

TIMP:

Tissue inhibitor of matrix metalloproteinases

TNFα:

Tumor necrosis factor alpha

VC:

Vascular calcification

VDRAs:

Vitamin D receptor activators

VEGF:

Vascular endothelial growth factor

Vit D3:

Vitamin D3

Vit K:

Vitamin K

Vit K2:

Vitamin K2

VSMCs:

Vascular smooth muscle cells

References

  1. Ketteler M, Schlieper G, Floege J. Calcification and cardiovascular health – new insights into an old phenomenon. Hypertension. 2006;47(6):1027–34.

    Article  CAS  PubMed  Google Scholar 

  2. Schlieper G, Schurgers L, Brandenburg V, Reutelingsperger C, Floege J. Vascular calcification in chronic kidney disease: an update. Nephrol Dial Transplant. 2015;31:31.

    Article  PubMed  CAS  Google Scholar 

  3. Schlieper G, Hess K, Floege J, Marx N. The vulnerable patient with chronic kidney disease. Nephrol Dial Transplant. 2015;31:382.

    Article  PubMed  Google Scholar 

  4. Moe SM, Chen NX. Mechanisms of vascular calcification in chronic kidney disease. J Am Soc Nephrol. 2008;19(2):213–6.

    Article  CAS  PubMed  Google Scholar 

  5. Lehto S, Niskanen L, Suhonen M, Rönnemaa T, Laakso M. Medial artery calcification: a neglected harbinger of cardiovascular complications in non–insulin-dependent diabetes mellitus. Arterioscler Thromb Vasc Biol. 1996;16(8):978–83.

    Article  CAS  PubMed  Google Scholar 

  6. Lanzer P, Boehm M, Sorribas V, Thiriet M, Janzen J, Zeller T, et al. Medial vascular calcification revisited: review and perspectives. Eur Heart J. 2014;35(23):1515–U24.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Mizobuchi M, Towler D, Slatopolsky E. vascular calcification: the killer of patients with chronic kidney disease. J Am Soc Nephrol. 2009;20(7):1453–64.

    Article  CAS  PubMed  Google Scholar 

  8. Rogers M, Goettsch C, Aikawa E. Medial and intimal calcification in chronic kidney disease: stressing the contributions. Am Heart Assoc. 2013;2:e000481.

    Article  CAS  Google Scholar 

  9. Savage T, Clarke AL, Giles M, Tomson CR, Raine AE. Calcified plaque is common in the carotid and femoral arteries of dialysis patients without clinical vascular disease. Nephrol Dial Transplant. 1998;13(8):2004–12.

    Article  CAS  PubMed  Google Scholar 

  10. London GM, Guerin AP, Marchais SJ, Metivier F, Pannier B, Adda H. Arterial media calcification in end-stage renal disease: impact on all-cause and cardiovascular mortality. Nephrol Dial Transplant. 2003;18(9):1731–40.

    Article  PubMed  Google Scholar 

  11. Blausen S.com staff. Medical gallery of Blausen Medical 2014. WikiJ Med. 2014;1(2):10.

    Google Scholar 

  12. Cocciolone AJ, Hawes JZ, Staiculescu MC, Johnson EO, Murshed M, Wagenseil JE. Elastin, arterial mechanics, and cardiovascular disease. Am J Physiol Heart Circ Physiol. 2018;315(2):H189–205.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Dingemans KP, Teeling P, Lagendijk JH, Becker AE. Extracellular matrix of the human aortic media: an ultrastructural histochemical and immunohistochemical study of the adult aortic media. Anat Rec. 2000;258(1):1–14.

    Article  CAS  PubMed  Google Scholar 

  14. El-Hamamsy I, Yacoub MH. Cellular and molecular mechanisms of thoracic aortic aneurysms. Nat Rev Cardiol. 2009;6(12):771.

    Article  CAS  PubMed  Google Scholar 

  15. Wolinsky H. Comparison of medial growth of human thoracic and abdominal aortas. Circ Res. 1970;27(4):531–8.

    Article  CAS  PubMed  Google Scholar 

  16. Karnik SK, Wythe JD, Sorensen L, Brooke BS, Urness LD, Li DY. Elastin induces myofibrillogenesis via a specific domain, VGVAPG. Matrix Biol. 2003;22(5):409–25.

    Article  CAS  PubMed  Google Scholar 

  17. Maleszewski J, Lai C, Veinot J. Anatomic considerations and examination of cardiovascular specimens (excluding devices). In: Cardiovascular pathology. New York: Elsevier; 2016. p. 1–56.

    Google Scholar 

  18. Cecelja M, Chowienczyk P. Role of arterial stiffness in cardiovascular disease. JRSM Cardiovasc Dis. 2012;1(4):1–10.

    Article  Google Scholar 

  19. Kim J, Staiculescu MC, Cocciolone AJ, Yanagisawa H, Mecham RP, Wagenseil JE. Crosslinked elastic fibers are necessary for low energy loss in the ascending aorta. J Biomech. 2017;61:199–207.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Lacolley P, Regnault V, Segers P, Laurent S. Vascular smooth muscle cells and arterial stiffening: relevance in development, aging, and disease. Physiol Rev. 2017;97(4):1555–617.

    Article  CAS  PubMed  Google Scholar 

  21. Sage H, Gray W. Studies on the evolution of elastin – I. Phylogenetic distribution. Comp Biochem Physiol B. 1979;64(4):313–27.

    Article  CAS  PubMed  Google Scholar 

  22. Wagenseil JE, Mecham RP. Elastin in large artery stiffness and hypertension. J Cardiovasc Transl Res. 2012;5(3):264–73.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Parks WC, Secrist H, Wu LC, Mecham R. Developmental regulation of tropoelastin isoforms. J Biol Chem. 1988;263(9):4416–23.

    Article  CAS  PubMed  Google Scholar 

  24. Phinikaridou A, Lacerda S, Lavin B, Andia ME, Smith A, Saha P, et al. Tropoelastin: a novel marker for plaque progression and instability. Circ Cardiovasc Imaging. 2018;11(8):e007303.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Krettek A, Sukhova GK, Libby P. Elastogenesis in human arterial disease: a role for macrophages in disordered elastin synthesis. Arterioscler Thromb Vasc Biol. 2003;23(4):582–7.

    Article  CAS  PubMed  Google Scholar 

  26. Greenwald S. Ageing of the conduit arteries. J Pathol. 2007;211(2):157–72.

    Article  CAS  PubMed  Google Scholar 

  27. Asmar R, Benetos A, Topouchian J, Laurent P, Pannier B, Brisac A-M, et al. Assessment of arterial distensibility by automatic pulse wave velocity measurement: validation and clinical application studies. Hypertension. 1995;26(3):485–90.

    Article  CAS  PubMed  Google Scholar 

  28. Kielty CM, Sherratt MJ, Shuttleworth CA. Elastic fibres. J Cell Sci. 2002;115(14):2817–28.

    Article  CAS  PubMed  Google Scholar 

  29. Hungerford JE, Owens GK, Argraves WS, Little CD. Development of the aortic vessel wall as defined by vascular smooth muscle and extracellular matrix markers. Dev Biol. 1996;178(2):375–92.

    Article  CAS  PubMed  Google Scholar 

  30. Argraves WS, Greene LM, Cooley MA, Gallagher WM. Fibulins: physiological and disease perspectives. EMBO Rep. 2003;4(12):1127–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Vrhovski B, Weiss AS. Biochemistry of tropoelastin. Eur J Biochem. 1998;258(1):1–18.

    Article  CAS  PubMed  Google Scholar 

  32. Starcher BC. Determination of the elastin content of tissues by measuring desmosine and isodesmosine. Anal Biochem. 1977;79(1–2):11–5.

    Article  CAS  PubMed  Google Scholar 

  33. Pereira L, Andrikopoulos K, Tian J, Lee SY, Keene DR, Ono R, et al. Targetting of the gene encoding fibrillin–1 recapitulates the vascular aspect of Marfan syndrome. Nat Genet. 1997;17(2):218.

    Article  CAS  PubMed  Google Scholar 

  34. Zhang H, Hu W, Ramirez F. Developmental expression of fibrillin genes suggests heterogeneity of extracellular microfibrils. J Cell Biol. 1995;129(4):1165–76.

    Article  CAS  PubMed  Google Scholar 

  35. Pereira L, Lee SY, Gayraud B, Andrikopoulos K, Shapiro SD, Bunton T, et al. Pathogenetic sequence for aneurysm revealed in mice underexpressing fibrillin-1. Proc Natl Acad Sci. 1999;96(7):3819–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Sherratt MJ. Tissue elasticity and the ageing elastic fibre. Age (Dordr). 2009;31(4):305–25.

    Article  CAS  Google Scholar 

  37. Massam-Wu T, Chiu M, Choudhury R, Chaudhry SS, Baldwin AK, McGovern A, et al. Assembly of fibrillin microfibrils governs extracellular deposition of latent TGFβ. J Cell Sci. 2010;123(17):3006–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Robertson IB, Rifkin DB. Regulation of the bioavailability of TGF-β and TGF-β-related proteins. Cold Spring Harb Perspect Biol. 2016;8(6):a021907.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Luo G, Ducy P, McKee MD, Pinero GJ, Loyer E, Behringer RR, et al. Spontaneous calcification of arteries and cartilage in mice lacking matrix GLA protein. Nature. 1997;386(6620):78.

    Article  CAS  PubMed  Google Scholar 

  40. Urry D. Neutral sites for calcium ion binding to elastin and collagen: a charge neutralization theory for calcification and its relationship to atherosclerosis. Proc Natl Acad Sci. 1971;68(4):810–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Sinha A, Vyavahare NR. High-glucose levels and elastin degradation products accelerate osteogenesis in vascular smooth muscle cells. Diab Vasc Dis Res. 2013;10(5):410–9.

    Article  CAS  PubMed  Google Scholar 

  42. Duca L, Floquet N, Alix AJ, Haye B, Debelle L. Elastin as a matrikine. Crit Rev Oncol Hematol. 2004;49(3):235–44.

    Article  PubMed  Google Scholar 

  43. Blaise S, Romier B, Kawecki C, Ghirardi M, Rabenoelina F, Baud S, et al. Elastin-derived peptides are new regulators of insulin resistance development in mice. Diabetes. 2013;62(11):3807–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Simionescu D, Simionescu A, Deac R. Detection of remnant proteolytic activities in unimplanted glutaraldehyde-treated bovine pericardium and explanted cardiac bioprostheses. J Biomed Mater Res. 1993;27(6):821–9.

    Article  CAS  PubMed  Google Scholar 

  45. Vyavahare N, Jones PL, Tallapragada S, Levy RJ. Inhibition of matrix metalloproteinase activity attenuates tenascin-C production and calcification of implanted purified elastin in rats. Am J Pathol. 2000;157(3):885–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Wang M, Kim SH, Monticone RE, Lakatta EG. Matrix metalloproteinases promote arterial remodeling in aging, hypertension, and atherosclerosis. Hypertension. 2015;65(4):698–703.

    Article  CAS  PubMed  Google Scholar 

  47. Vyavahare N, Ogle M, Schoen FJ, Levy RJ. Elastin calcification and its prevention with aluminum chloride pretreatment. Am J Pathol. 1999;155(3):973–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Basalyga DM, Simionescu DT, Xiong W, Baxter BT, Starcher BC, Vyavahare NR. Elastin degradation and calcification in an abdominal aorta injury model: role of matrix metalloproteinases. Circulation. 2004;110(22):3480–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Lemaître V, Soloway PD, D’Armiento J. Increased medial degradation with pseudo-aneurysm formation in apolipoprotein E–knockout mice deficient in tissue inhibitor of metalloproteinases-1. Circulation. 2003;107(2):333–8.

    Article  PubMed  CAS  Google Scholar 

  50. Sukhova GK, Wang B, Libby P, Pan J-H, Zhang Y, Grubb A, et al. Cystatin C deficiency increases elastic lamina degradation and aortic dilatation in apolipoprotein E–null mice. Circ Res. 2005;96(3):368–75.

    Article  CAS  PubMed  Google Scholar 

  51. Cheng XW, Huang Z, Kuzuya M, Okumura K, Murohara T. Cysteine protease cathepsins in atherosclerosis-based vascular disease and its complications. Hypertension. 2011;58(6):978–86.

    Article  CAS  PubMed  Google Scholar 

  52. Fonovic M, Turk B. Cysteine cathepsins and extracellular matrix degradation. Biochim Biophys Acta. 2014;1840(8):2560–70.

    Article  CAS  PubMed  Google Scholar 

  53. Aikawa E, Aikawa M, Libby P, Figueiredo JL, Rusanescu G, Iwamoto Y, et al. Arterial and aortic valve calcification abolished by elastolytic cathepsin S deficiency in chronic renal disease. Circulation. 2009;119(13):1785–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Andrault P-M, Panwar P, Mackenzie NC, Brömme D. Elastolytic activity of cysteine cathepsins K, S, and V promotes vascular calcification. Sci Rep. 2019;9(1):9682.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. New SE, Goettsch C, Aikawa M, Marchini JF, Shibasaki M, Yabusaki K, et al. Macrophage-derived matrix vesicles: an alternative novel mechanism for microcalcification in atherosclerotic plaques. Circ Res. 2013;113(1):72–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Hutcheson JD, Goettsch C, Bertazzo S, Maldonado N, Ruiz JL, Goh W, et al. Genesis and growth of extracellular-vesicle-derived microcalcification in atherosclerotic plaques. Nat Mater. 2016;15(3):335.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Dale MA, Xiong W, Carson JS, Suh MK, Karpisek AD, Meisinger TM, et al. Elastin-derived peptides promote abdominal aortic aneurysm formation by modulating M1/M2 macrophage polarization. J Immunol. 2016;196(11):4536–43.

    Article  CAS  PubMed  Google Scholar 

  58. Matt P, Schoenhoff F, Habashi J, Holm T, Van Erp C, Loch D, et al. Circulating TGFβ in Marfan’s syndrome. Circulation. 2009;120(6):526.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Hanada K, Vermeij M, Garinis GA, De Waard MC, Kunen MG, Myers L, et al. Perturbations of vascular homeostasis and aortic valve abnormalities in fibulin-4 deficient mice. Circ Res. 2007;100(5):738–46.

    Article  CAS  PubMed  Google Scholar 

  60. Bouvet C, Moreau S, Blanchette J, de Blois D, Moreau P. Sequential activation of matrix metalloproteinase 9 and transforming growth factor β in arterial elastocalcinosis. Arterioscler Thromb Vasc Biol. 2008;28(5):856–62.

    Article  CAS  PubMed  Google Scholar 

  61. Lansing AI, Alex M, Rosenthal TB. Calcium and elastin in human arteriosclerosis. J Gerontol. 1950;5(2):112–9.

    Article  CAS  PubMed  Google Scholar 

  62. Bobryshev YV. Calcification of elastic fibers in human atherosclerotic plaque. Atherosclerosis. 2005;180(2):293–303.

    Article  CAS  PubMed  Google Scholar 

  63. Gayral S, Garnotel R, Castaing-Berthou A, Blaise S, Fougerat A, Berge E, et al. Elastin-derived peptides potentiate atherosclerosis through the immune Neu1–PI3Kγ pathway. Cardiovasc Res. 2013;102(1):118–27.

    Article  PubMed  CAS  Google Scholar 

  64. Galis ZS, Khatri JJ. Matrix metalloproteinases in vascular remodeling and atherogenesis: the good, the bad, and the ugly. Circ Res. 2002;90(3):251–62.

    Article  CAS  PubMed  Google Scholar 

  65. Sukhova GK, Shi G-P, Simon DI, Chapman HA, Libby P. Expression of the elastolytic cathepsins S and K in human atheroma and regulation of their production in smooth muscle cells. J Clin Invest. 1998;102(3):576–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Rodgers KJ, Watkins DJ, Miller AL, Chan PY, Karanam S, Brissette WH, et al. Destabilizing role of cathepsin S in murine atherosclerotic plaques. Arterioscler Thromb Vasc Biol. 2006;26(4):851–6.

    Article  CAS  PubMed  Google Scholar 

  67. Li DY, Brooke B, Davis EC, Mecham RP, Sorensen LK, Boak BB, et al. Elastin is an essential determinant of arterial morphogenesis. Nature. 1998;393(6682):276.

    Article  CAS  PubMed  Google Scholar 

  68. Bennett MR, Sinha S, Owens GK. Vascular smooth muscle cells in atherosclerosis. Circ Res. 2016;118(4):692–702.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Pai AS, Giachelli CM. Matrix remodeling in vascular calcification associated with chronic kidney disease. J Am Soc Nephrol. 2010;21(10):1637–40.

    Article  PubMed  Google Scholar 

  70. Dudenbostel T, Glasser SP. Effects of antihypertensive drugs on arterial stiffness. Cardiol Rev. 2012;20(5):259.

    Article  PubMed  Google Scholar 

  71. Rattazzi M, Bertacco E, Puato M, Faggin E, Pauletto P. Hypertension and vascular calcification: a vicious cycle? J Hypertens. 2012;30(10):1885–93.

    Article  CAS  PubMed  Google Scholar 

  72. Maahs DM, Snell-Bergeon JK, Kinney GL, Wadwa RP, Garg S, Ogden LG, et al. ACE-I/ARB treatment in type 1 diabetes patients with albuminuria is associated with lower odds of progression of coronary artery calcification. J Diabetes Complicat. 2007;21(5):273–9.

    Article  Google Scholar 

  73. Block GA, Spiegel DM, Ehrlich J, Mehta R, Lindbergh J, Dreisbach A, et al. Effects of sevelamer and calcium on coronary artery calcification in patients new to hemodialysis. Kidney Int. 2005;68(4):1815–24.

    Article  CAS  PubMed  Google Scholar 

  74. Teng M, Wolf M, Lowrie E, Ofsthun N, Lazarus JM, Thadhani R. Survival of patients undergoing hemodialysis with paricalcitol or calcitriol therapy. N Engl J Med. 2003;349(5):446–56.

    Article  CAS  PubMed  Google Scholar 

  75. Tentori F, Hunt W, Stidley C, Rohrscheib M, Bedrick E, Meyer K, et al. Mortality risk among hemodialysis patients receiving different vitamin D analogs. Kidney Int. 2006;70(10):1858–65.

    Article  CAS  PubMed  Google Scholar 

  76. Sprague SM, Llach F, Amdahl M, Taccetta C, Batlle D. Paricalcitol versus calcitriol in the treatment of secondary hyperparathyroidism. Kidney Int. 2003;63(4):1483–90.

    Article  CAS  PubMed  Google Scholar 

  77. Raggi P, Chertow GM, Torres PU, Csiky B, Naso A, Nossuli K, et al. The ADVANCE study: a randomized study to evaluate the effects of cinacalcet plus low-dose vitamin D on vascular calcification in patients on hemodialysis. Nephrol Dial Transplant. 2010;26(4):1327–39.

    Article  PubMed  CAS  Google Scholar 

  78. Investigators ET. Effect of cinacalcet on cardiovascular disease in patients undergoing dialysis. N Engl J Med. 2012;367(26):2482–94.

    Article  Google Scholar 

  79. Bleyer AJ, Burkart J, Piazza M, Russell G, Rohr M, Carr JJ. Changes in cardiovascular calcification after parathyroidectomy in patients with ESRD. Am J Kidney Dis. 2005;46(3):464–9.

    Article  PubMed  Google Scholar 

  80. Iwamoto N, Sato N, Nishida M, Hashimoto T, Kobayashi H, Yamasaki S, et al. Total parathyroidectomy improves survival of hemodialysis patients with secondary hyperparathyroidism. J Nephrol. 2012;25(5):755–63.

    Article  CAS  PubMed  Google Scholar 

  81. Price PA, Faus SA, Williamson MK. Bisphosphonates alendronate and ibandronate inhibit artery calcification at doses comparable to those that inhibit bone resorption. Arterioscler Thromb Vasc Biol. 2001;21(5):817–24.

    Article  CAS  PubMed  Google Scholar 

  82. Neven EG, De Broe ME, d’Haese PC. Prevention of vascular calcification with bisphosphonates without affecting bone mineralization: a new challenge? Kidney Int. 2009;75(6):580–2.

    Article  CAS  PubMed  Google Scholar 

  83. Rapoport HS, Connolly JM, Fulmer J, Dai N, Murti BH, Gorman RC, et al. Mechanisms of the in vivo inhibition of calcification of bioprosthetic porcine aortic valve cusps and aortic wall with triglycidylamine/mercapto bisphosphonate. Biomaterials. 2007;28(4):690–9.

    Article  CAS  PubMed  Google Scholar 

  84. Bucay N, Sarosi I, Dunstan CR, Morony S, Tarpley J, Capparelli C, et al. Osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev. 1998;12(9):1260–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Helas S, Goettsch C, Schoppet M, Zeitz U, Hempel U, Morawietz H, et al. Inhibition of receptor activator of NF-κB ligand by denosumab attenuates vascular calcium deposition in mice. Am J Pathol. 2009;175(2):473–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Nitta K, Akiba T, Suzuki K, Uchida K, Watanabe R-I, Majima K, et al. Effects of cyclic intermittent etidronate therapy on coronary artery calcification in patients receiving long-term hemodialysis. Am J Kidney Dis. 2004;44(4):680–8.

    Article  CAS  PubMed  Google Scholar 

  87. Toussaint ND, Lau KK, Strauss BJ, Polkinghorne KR, Kerr PG. Effect of alendronate on vascular calcification in CKD stages 3 and 4: a pilot randomized controlled trial. Am J Kidney Dis. 2010;56(1):57–68.

    Article  CAS  PubMed  Google Scholar 

  88. Simpson CL, Lindley S, Eisenberg C, Basalyga DM, Starcher BC, Simionescu DT, et al. Toward cell therapy for vascular calcification: osteoclast-mediated demineralization of calcified elastin. Cardiovasc Pathol. 2007;16(1):29–37.

    Article  CAS  PubMed  Google Scholar 

  89. Wu M, Rementer C, Giachelli CM. Vascular calcification: an update on mechanisms and challenges in treatment. Calcif Tissue Int. 2013;93(4):365–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Adirekkiat S, Sumethkul V, Ingsathit A, Domrongkitchaiporn S, Phakdeekitcharoen B, Kantachuvesiri S, et al. Sodium thiosulfate delays the progression of coronary artery calcification in haemodialysis patients. Nephrol Dial Transplant. 2010;25(6):1923–9.

    Article  CAS  PubMed  Google Scholar 

  91. Mathews SJ, De Las FL, Podaralla P, Cabellon A, Zheng S, Bierhals A, et al. Effects of sodium thiosulfate on vascular calcification in end-stage renal disease: a pilot study of feasibility, safety and efficacy. Am J Nephrol. 2011;33(2):131–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Shao J-S, Cheng S-L, Charlton-Kachigian N, Loewy AP, Towler DA. Teriparatide (human parathyroid hormone (1–34)) inhibits osteogenic vascular calcification in diabetic low density lipoprotein receptor-deficient mice. J Biol Chem. 2003;278(50):50195–202.

    Article  CAS  PubMed  Google Scholar 

  93. Brodeur MR, Bouvet C, Bouchard S, Moreau S, Leblond J, deBlois D, et al. Reduction of advanced-glycation end products levels and inhibition of RAGE signaling decreases rat vascular calcification induced by diabetes. PLoS ONE. 2014;9(1):e85922.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. Zhou Y-B, Zhou H, Li L, Kang Y, Cao X, Wu Z-Y, et al. Hydrogen sulfide prevents elastin loss and attenuates calcification induced by high glucose in smooth muscle cells through suppression of Stat3/Cathepsin S signaling pathway. Int J Mol Sci. 2019;20(17):4202.

    Article  PubMed Central  CAS  Google Scholar 

  95. Cheng S-L, Ramachandran B, Behrmann A, Shao J-S, Mead M, Smith C, et al. Vascular smooth muscle LRP6 limits arteriosclerotic calcification in diabetic LDLR−/− mice by restraining noncanonical Wnt signals. Circ Res. 2015;117(2):142–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Cheng S-L, Behrmann A, Shao J-S, Ramachandran B, Krchma K, Arredondo YB, et al. Targeted reduction of vascular Msx1 and Msx2 mitigates arteriosclerotic calcification and aortic stiffness in LDLR-deficient mice fed diabetogenic diets. Diabetes. 2014;63(12):4326–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Dube PR, Chikkamenahalli LL, Birnbaumer L, Vazquez G. Reduced calcification and osteogenic features in advanced atherosclerotic plaques of mice with macrophage-specific loss of TRPC3. Atherosclerosis. 2018;270:199–204.

    Article  CAS  PubMed  Google Scholar 

  98. Bruining N, de Winter S, Roelandt JR, Rodriguez-Granillo GA, Heller I, van Domburg RT, et al. Coronary calcium significantly affects quantitative analysis of coronary ultrasound: importance for atherosclerosis progression/regression studies. Coron Artery Dis. 2009;20(6):409–14.

    Article  PubMed  Google Scholar 

  99. Maniscalco BS, Taylor KA. Calcification in coronary artery disease can be reversed by EDTA–tetracycline long-term chemotherapy. Pathophysiology. 2004;11(2):95–101.

    Article  CAS  PubMed  Google Scholar 

  100. Otto CM. Heartbeat: highlights from this issue. BMJ: Publishing Group Ltd./British Cardiovascular Society; 2015.

    Google Scholar 

  101. Abedin M, Lim J, Tang T, Park D, Demer L, Tintut Y. N-3 fatty acids inhibit vascular calcification via the p38-mitogen-activated protein kinase and peroxisome proliferator-activated receptor-γ pathways. Circ Res. 2006;98(6):727–9.

    Article  CAS  PubMed  Google Scholar 

  102. Lei Y, Grover A, Sinha A, Vyavahare N. Efficacy of reversal of aortic calcification by chelating agents. Calcif Tissue Int. 2013;93(5):426–35.

    Article  CAS  PubMed  Google Scholar 

  103. Lamas GA, Goertz C, Boineau R, Mark DB, Rozema T, Nahin RL, et al. Effect of disodium EDTA chelation regimen on cardiovascular events in patients with previous myocardial infarction: the TACT randomized trial. JAMA. 2013;309(12):1241–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Escolar E, Lamas GA, Mark DB, Boineau R, Goertz C, Rosenberg Y, et al. The effect of an EDTA-based chelation regimen on patients with diabetes mellitus and prior myocardial infarction in the trial to assess chelation therapy (TACT). Circulation. 2014;7(1):15–24.

    PubMed  Google Scholar 

  105. Atwood KC IV, Woeckner E, Baratz RS, Sampson WI. Why the NIH trial to assess chelation therapy (TACT) should be abandoned. Medscape J Med. 2008;10(5):115.

    PubMed  PubMed Central  Google Scholar 

  106. Sinha A, Shaporev A, Nosoudi N, Lei Y, Vertegel A, Lessner S, et al. Nanoparticle targeting to diseased vasculature for imaging and therapy. Nanomedicine. 2014;10(5):e1003–e12.

    Article  CAS  Google Scholar 

  107. Lei Y, Nosoudi N, Vyavahare N. Targeted chelation therapy with EDTA-loaded albumin nanoparticles regresses arterial calcification without causing systemic side effects. J Control Release. 2014;196:79–86.

    Article  CAS  PubMed  Google Scholar 

  108. Nosoudi N, Chowdhury A, Siclari S, Karamched S, Parasaram V, Parrish J, et al. Reversal of vascular calcification and aneurysms in a rat model using dual targeted therapy with EDTA-and PGG-loaded nanoparticles. Theranostics. 2016;6(11):1975.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Sinha A, Nosoudi N, Vyavahare N. Elasto-regenerative properties of polyphenols. Biochem Biophys Res Commun. 2014;444(2):205–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Karamched SR, Nosoudi N, Moreland HE, Chowdhury A, Vyavahare NR. Site-specific chelation therapy with EDTA-loaded albumin nanoparticles reverses arterial calcification in a rat model of chronic kidney disease. Sci Rep. 2019;9(1):2629.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  111. Zhou P, Zhang X, Guo M, Guo R, Wang L, Zhang Z, et al. Ginsenoside Rb1 ameliorates CKD-associated vascular calcification by inhibiting the Wnt/β-catenin pathway. J Cell Mol Med. 2019;23:7088.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Mathew S, Lund RJ, Strebeck F, Tustison KS, Geurs T, Hruska KA. Reversal of the adynamic bone disorder and decreased vascular calcification in chronic kidney disease by sevelamer carbonate therapy. J Am Soc Nephrol. 2007;18(1):122–30.

    Article  CAS  PubMed  Google Scholar 

  113. Lin T, Wang X-L, Zettervall SL, Cai Y, Guzman RJ. Dorsomorphin homologue 1, a highly selective small-molecule bone morphogenetic protein inhibitor, suppresses medial artery calcification. J Vasc Surg. 2017;66(2):586–93.

    Article  PubMed  Google Scholar 

  114. Kim H, Kim HJ, Lee K, Kim JM, Kim HS, Kim JR, et al. α-Lipoic acid attenuates vascular calcification via reversal of mitochondrial function and restoration of Gas6/Axl/Akt survival pathway. J Cell Mol Med. 2012;16(2):273–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. de Oca AM, Guerrero F, Martinez-Moreno JM, Madueno JA, Herencia C, Peralta A, et al. Magnesium inhibits Wnt/β-catenin activity and reverses the osteogenic transformation of vascular smooth muscle cells. PLoS ONE. 2014;9(2):e89525.

    Article  CAS  Google Scholar 

  116. Mathew S, Lund RJ, Chaudhary LR, Geurs T, Hruska KA. Vitamin D receptor activators can protect against vascular calcification. J Am Soc Nephrol. 2008;19(8):1509–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Lomashvili KA, Monier-Faugere M-C, Wang X, Malluche HH, O’neill WC. Effect of bisphosphonates on vascular calcification and bone metabolism in experimental renal failure. Kidney Int. 2009;75(6):617–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Davies MR, Lund RJ, Hruska KA. BMP-7 is an efficacious treatment of vascular calcification in a murine model of atherosclerosis and chronic renal failure. J Am Soc Nephrol. 2003;14(6):1559–67.

    Article  PubMed  Google Scholar 

  119. Qin X, Corriere MA, Matrisian LM, Guzman RJ. Matrix metalloproteinase inhibition attenuates aortic calcification. Arterioscler Thromb Vasc Biol. 2006;26(7):1510–6.

    Article  CAS  PubMed  Google Scholar 

  120. O’neill WC, Lomashvili KA, Malluche HH, Faugere M-C, Riser BL. Treatment with pyrophosphate inhibits uremic vascular calcification. Kidney Int. 2011;79(5):512–7.

    Article  PubMed  CAS  Google Scholar 

  121. Mataic D, Bastani B. Intraperitoneal sodium thiosulfate for the treatment of calciphylaxis. Ren Fail. 2006;28(4):361–3.

    Article  PubMed  Google Scholar 

  122. Bas A, Lopez I, Perez J, Rodriguez M, Aguilera-Tejero E. Reversibility of calcitriol-induced medial artery calcification in rats with intact renal function. J Bone Miner Res. 2006;21(3):484–90.

    Article  CAS  PubMed  Google Scholar 

  123. Cai Y, Xu M-J, Teng X, Zhou YB, Chen L, Zhu Y, et al. Intermedin inhibits vascular calcification by increasing the level of matrix γ-carboxyglutamic acid protein. Cardiovasc Res. 2009;85(4):864–73.

    Article  PubMed  CAS  Google Scholar 

  124. Dai X-Y, Zhao M-M, Cai Y, Guan Q-C, Zhao Y, Guan Y, et al. Phosphate-induced autophagy counteracts vascular calcification by reducing matrix vesicle release. Kidney Int. 2013;83(6):1042–51.

    Article  CAS  PubMed  Google Scholar 

  125. Cao X, Li H, Tao H, Wu N, Yu L, Zhang D, et al. Metformin inhibits vascular calcification in female rat aortic smooth muscle cells via the AMPK-eNOS-NO pathway. Endocrinology. 2013;154(10):3680–9.

    Article  CAS  PubMed  Google Scholar 

  126. Cui L, Li Z, Chang X, Cong G, Hao L. Quercetin attenuates vascular calcification by inhibiting oxidative stress and mitochondrial fission. Vasc Pharmacol. 2017;88:21–9.

    Article  CAS  Google Scholar 

  127. Ohnishi M, Nakatani T, Lanske B, Razzaque MS. In vivo genetic evidence for suppressing vascular and soft-tissue calcification through the reduction of serum phosphate levels, even in the presence of high serum calcium and 1, 25-dihydroxyvitamin d levels. Circ Cardiovasc Genet. 2009;2(6):583–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Wu SY, Pan CS, Geng B, Zhao J, Yu F, YZ PANG, et al. Hydrogen sulfide ameliorates vascular calcification induced by vitamin D3 plus nicotine in rats 1. Acta Pharmacol Sin. 2006;27(3):299–306.

    Article  CAS  PubMed  Google Scholar 

  129. Leibrock CB, Feger M, Voelkl J, Kohlhofer U, Quintanilla-Martinez L, Kuro-o M, et al. Partial reversal of tissue calcification and extension of life span following ammonium nitrate treatment of klotho-deficient mice. Kidney Blood Press Res. 2016;41(1):99–107.

    Article  CAS  PubMed  Google Scholar 

  130. Reynolds JL, Skepper JN, McNair R, Kasama T, Gupta K, Weissberg PL, et al. Multifunctional roles for serum protein fetuin-a in inhibition of human vascular smooth muscle cell calcification. J Am Soc Nephrol. 2005;16(10):2920–30.

    Article  CAS  PubMed  Google Scholar 

  131. Son B-K, Kozaki K, Iijima K, Eto M, Nakano T, Akishita M, et al. Gas6/Axl-PI3K/Akt pathway plays a central role in the effect of statins on inorganic phosphate-induced calcification of vascular smooth muscle cells. Eur J Pharmacol. 2007;556(1–3):1–8.

    Article  CAS  PubMed  Google Scholar 

  132. Westenfeld R, Schäfer C, Krüger T, Haarmann C, Schurgers LJ, Reutelingsperger C, et al. Fetuin-A protects against atherosclerotic calcification in CKD. J Am Soc Nephrol. 2009;20(6):1264–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Lee K, Kim H, Jeong D. Microtubule stabilization attenuates vascular calcification through the inhibition of osteogenic signaling and matrix vesicle release. Biochem Biophys Res Commun. 2014;451(3):436–41.

    Article  CAS  PubMed  Google Scholar 

  134. Cao F, Liu X, Cao X, Wang S, Fu K, Zhao Y, et al. Fibroblast growth factor 21 plays an inhibitory role in vascular calcification in vitro through OPG/RANKL system. Biochem Biophys Res Commun. 2017;491(3):578–86.

    Article  CAS  PubMed  Google Scholar 

  135. Duan X-Y, Xie P-L, Ma Y-L, Tang S-Y. Omentin inhibits osteoblastic differentiation of calcifying vascular smooth muscle cells through the PI3K/Akt pathway. Amino Acids. 2011;41(5):1223–31.

    Article  CAS  PubMed  Google Scholar 

  136. Kanai S, Uto K, Honda K, Hagiwara N, Oda H. Eicosapentaenoic acid reduces warfarin-induced arterial calcification in rats. Atherosclerosis. 2011;215(1):43–51.

    Article  CAS  PubMed  Google Scholar 

  137. Chang X, Zhang B, Lihua L, Feng Z. T3 inhibits the calcification of vascular smooth muscle cells and the potential mechanism. Am J Transl Res. 2016;8(11):4694.

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Jiang X, Tao H, Qiu C, Ma X, Li S, Guo X, et al. Vitamin K2 regression aortic calcification induced by warfarin via Gas6/Axl survival pathway in rats. Eur J Pharmacol. 2016;786:10–8.

    Article  CAS  PubMed  Google Scholar 

  139. Kawata T, Nagano N, Obi M, Miyata S, Koyama C, Kobayashi N, et al. Cinacalcet suppresses calcification of the aorta and heart in uremic rats. Kidney Int. 2008;74(10):1270–7.

    Article  CAS  PubMed  Google Scholar 

  140. Liu D, Cui W, Liu B, Hu H, Liu J, Xie R, et al. Atorvastatin protects vascular smooth muscle cells from TGF-β1-stimulated calcification by inducing autophagy via suppression of the β-catenin pathway. Cell Physiol Biochem. 2014;33(1):129–41.

    Article  PubMed  CAS  Google Scholar 

  141. Osako MK, Nakagami H, Koibuchi N, Shimizu H, Nakagami F, Koriyama H, et al. Estrogen inhibits vascular calcification via vascular RANKL system: common mechanism of osteoporosis and vascular calcification. Circ Res. 2010;107(4):466–75.

    Article  CAS  PubMed  Google Scholar 

  142. Essalihi R, Zandvliet ML, Moreau S, Gilbert L-A, Bouvet C, Lenoël C, et al. Distinct effects of amlodipine treatment on vascular elastocalcinosis and stiffness in a rat model of isolated systolic hypertension. J Hypertens. 2007;25(9):1879–86.

    Article  CAS  PubMed  Google Scholar 

  143. Takemura A, Iijima K, Ota H, Son B-K, Ito Y, Ogawa S, et al. Sirtuin 1 retards hyperphosphatemia-induced calcification of vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 2011;31(9):2054–62.

    Article  CAS  PubMed  Google Scholar 

  144. Luong TT, Schelski N, Boehme B, Makridakis M, Vlahou A, Lang F, et al. Fibulin-3 attenuates phosphate-induced vascular smooth muscle cell calcification by inhibition of oxidative stress. Cell Physiol Biochem. 2018;46(4):1305–16.

    Article  CAS  PubMed  Google Scholar 

  145. Neven E, Dams G, Postnov A, Chen B, De Clerck N, De Broe ME, et al. Adequate phosphate binding with lanthanum carbonate attenuates arterial calcification in chronic renal failure rats. Nephrol Dial Transplant. 2009;24(6):1790–9.

    Article  CAS  PubMed  Google Scholar 

  146. Tang F, Wu X, Wang T, Wang P, Li R, Zhang H, et al. Tanshinone II A attenuates atherosclerotic calcification in rat model by inhibition of oxidative stress. Vasc Pharmacol. 2007;46(6):427–38.

    Article  CAS  Google Scholar 

  147. Alesutan I, Musculus K, Castor T, Alzoubi K, Voelkl J, Lang F. Inhibition of phosphate-induced vascular smooth muscle cell osteo−/chondrogenic signaling and calcification by bafilomycin A1 and methylamine. Kidney Blood Press Res. 2015;40(5):490–9.

    Article  CAS  PubMed  Google Scholar 

  148. Kiffer-Moreira T, Yadav MC, Zhu D, Narisawa S, Sheen C, Stec B, et al. Pharmacological inhibition of PHOSPHO1 suppresses vascular smooth muscle cell calcification. J Bone Miner Res. 2013;28(1):81–91.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was funded in part by the National Institutes of Health (NIH) grants (R01HL145064, R01HL133662, P30GM131959, P20GM103444) and Hunter Endowment at Clemson University to NRV. Authors also acknowledge constructive discussion with Douglas Mulhall for preparation of this manuscript.

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Authors and Affiliations

  1. Bioengineering, Clemson University, Clemson, SC, USA

    Fatema-Tuj Zohora, Saketh Ram Karamched & Naren Vyavahare

  2. College of Information Technology and Engineering, Marshall University, Huntington, WV, USA

    Nasim Nosoudi

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  1. Fatema-Tuj Zohora
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  2. Nasim Nosoudi
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  3. Saketh Ram Karamched
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  4. Naren Vyavahare
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Correspondence to Naren Vyavahare .

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  1. Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Elena Aikawa

  2. Department of Biomedical Engineering, Florida International University, Miami, FL, USA

    Joshua D. Hutcheson

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Zohora, FT., Nosoudi, N., Karamched, S.R., Vyavahare, N. (2020). The Role of Elastin Degradation in Vascular Calcification: Possibilities to Repair Elastin and Reverse Calcification. In: Aikawa, E., Hutcheson, J. (eds) Cardiovascular Calcification and Bone Mineralization. Contemporary Cardiology. Humana, Cham. https://doi.org/10.1007/978-3-030-46725-8_20

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