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Molecular Mechanisms of Aortic Valve Pathology

  • Ghada Mkannez
  • Deborah Argaud
  • Marie-Chloé Boulanger
  • Patrick MathieuEmail author
Chapter

Abstract

The aortic valve is a dynamic structure composed of valve interstitial cells (VICs) and valve endothelial cells (VECs), which contribute to maintain and repair the extracellular matrix (ECM). Disorders of the aortic valve, such as calcific aortic valve disease (CAVD), are characterized by the re-expression of embryonic genes involved in valvulogenesis and actively participate to the pathologic remodeling of the ECM. Studies performed in the last several years have underlined that inflammation and lipid signaling pathways are intertwined in promoting the fibrocalcific remodeling process of the aortic valve. Altered blood flow dynamics along with genetic factors are involved in disorders associated with bicuspid aortic valve (BAV), a valve with two leaflets instead of three. The control of osteogenesis in the aortic valve is complex and involves different signaling cascades such as NF-κB, NOTCH, and Wnt pathways. In this chapter, we are reviewing the basic concepts related to the biology of the aortic valve and the pathobiology behind the development of CAVD and BAV.

Keywords

Aortic valve Valve interstitial cells Calcific aortic valve disease Aortic stenosis Bicuspid aortic valve Calcification Pathology 

Notes

Acknowledgments

The work of the authors is supported by Canadian Institutes of Health Research grants to P.M. (MOP114893, MOP114893, MOP114893, MOP365029), the Heart and Stroke Foundation of Canada, and the Quebec Heart and Lung Institute Fund. P.M. holds a FRQS Research Chair on the Pathobiology of Calcific Aortic Valve Disease.

References

  1. 1.
    Mathieu P, Boulanger MC. Basic mechanisms of calcific aortic valve disease. Can J Cardiol. 2014;30:982–93.CrossRefGoogle Scholar
  2. 2.
    Guauque-Olarte S, Messika-Zeitoun D, Droit A, Lamontagne M, Tremblay-Marchand J, Lavoie-Charland E, et al. Calcium signaling pathway genes RUNX2 and CACNA1C are associated with calcific aortic valve disease. Circ Cardiovasc Genet. 2015;8:812–22.CrossRefGoogle Scholar
  3. 3.
    Hinton RB, Yutzey KE. Heart valve structure and function in development and disease. Annu Rev Physiol. 2011;73:29–46.CrossRefGoogle Scholar
  4. 4.
    Wirrig EE, Yutzey KE. Conserved transcriptional regulatory mechanisms in aortic valve development and disease. Arterioscler Thromb Vasc Biol. 2014;34:737–41.CrossRefGoogle Scholar
  5. 5.
    Latif N, Sarathchandra P, Chester AH, Yacoub MH. Expression of smooth muscle cell markers and co-activators in calcified aortic valves. Eur Heart J. 2015;36:1335–45.CrossRefGoogle Scholar
  6. 6.
    Chen JH, Yip CY, Sone ED, Simmons CA. Identification and characterization of aortic valve mesenchymal progenitor cells with robust osteogenic calcification potential. Am J Pathol. 2009;174:1109–19.CrossRefGoogle Scholar
  7. 7.
    Mahler GJ, Farrar EJ, Butcher JT. Inflammatory cytokines promote mesenchymal transformation in embryonic and adult valve endothelial cells. Arterioscler Thromb Vasc Biol. 2013;33:121–30.CrossRefGoogle Scholar
  8. 8.
    Lincoln J, Yutzey KE. Molecular and developmental mechanisms of congenital heart valve disease. Birth Defects Res A Clin Mol Teratol. 2011;91:526–34.CrossRefGoogle Scholar
  9. 9.
    Hajdu Z, Romeo SJ, Fleming PA, Markwald RR, Visconti RP, Drake CJ. Recruitment of bone marrow-derived valve interstitial cells is a normal homeostatic process. J Mol Cell Cardiol. 2011;51:955–65.CrossRefGoogle Scholar
  10. 10.
    Nomura A, Seya K, Yu Z, Daitoku K, Motomura S, Murakami M, et al. CD34-negative mesenchymal stem-like cells may act as the cellular origin of human aortic valve calcification. Biochem Biophys Res Commun. 2013;440:780–5.CrossRefGoogle Scholar
  11. 11.
    Choi JH, Do Y, Cheong C, Koh H, Boscardin SB, Oh YS, et al. Identification of antigen-presenting dendritic cells in mouse aorta and cardiac valves. J Exp Med. 2009;206:497–505.CrossRefGoogle Scholar
  12. 12.
    Simmons CA, Grant GR, Manduchi E, Davies PF. Spatial heterogeneity of endothelial phenotypes correlates with side-specific vulnerability to calcification in normal porcine aortic valves. Circ Res. 2005;96:792–9.CrossRefGoogle Scholar
  13. 13.
    El-Hamamsy I, Balachandran K, Yacoub MH, Stevens LM, Sarathchandra P, Taylor PM, et al. Endothelium-dependent regulation of the mechanical properties of aortic valve cusps. J Am Coll Cardiol. 2009;53:1448–55.CrossRefGoogle Scholar
  14. 14.
    Richards J, El-Hamamsy I, Chen S, Sarang Z, Sarathchandra P, Yacoub MH, et al. Side-specific endothelial-dependent regulation of aortic valve calcification: interplay of hemodynamics and nitric oxide signaling. Am J Pathol. 2013;182:1922–31.CrossRefGoogle Scholar
  15. 15.
    Bosse K, Hans CP, Zhao N, Koenig SN, Huang N, Guggilam A, et al. Endothelial nitric oxide signaling regulates Notch1 in aortic valve disease. J Mol Cell Cardiol. 2013;60:27–35.CrossRefGoogle Scholar
  16. 16.
    Rajamannan NM, Evans FJ, Aikawa E, Grande-Allen KJ, Demer LL, Heistad DD, et al. Calcific aortic valve disease: not simply a degenerative process: a review and agenda for research from the National Heart and Lung and Blood Institute Aortic Stenosis Working Group. Executive summary: calcific aortic valve disease-2011 update. Circulation. 2011;124:1783–91.CrossRefGoogle Scholar
  17. 17.
    Lindman BR, Clavel MA, Mathieu P, Iung B, Lancellotti P, Otto CM, et al. Calcific aortic stenosis. Nat Rev Dis Primers. 2016;2:16006.CrossRefGoogle Scholar
  18. 18.
    Cote N, Mahmut A, Bosse Y, Couture C, Page S, Trahan S, et al. Inflammation is associated with the remodeling of calcific aortic valve disease. Inflammation. 2013;36:573–81.CrossRefGoogle Scholar
  19. 19.
    Akahori H, Tsujino T, Naito Y, Yoshida C, Lee-Kawabata M, Ohyanagi M, et al. Intraleaflet haemorrhage as a mechanism of rapid progression of stenosis in bicuspid aortic valve. Int J Cardiol. 2013;167:514–8.CrossRefGoogle Scholar
  20. 20.
    Laguna-Fernandez A, Carracedo M, Jeanson G, Nagy E, Eriksson P, Caligiuri G, et al. Iron alters valvular interstitial cell function and is associated with calcification in aortic stenosis. Eur Heart J. 2016;37:3532–5.CrossRefGoogle Scholar
  21. 21.
    O'Brien KD, Reichenbach DD, Marcovina SM, Kuusisto J, Alpers CE, Otto CM. Apolipoproteins B, (a), and E accumulate in the morphologically early lesion of ‘degenerative’ valvular aortic stenosis. Arterioscler Thromb Vasc Biol. 1996;16:523–32.CrossRefGoogle Scholar
  22. 22.
    Thanassoulis G, Campbell CY, Owens DS, Smith JG, Smith AV, Peloso GM, et al. Genetic associations with valvular calcification and aortic stenosis. N Engl J Med. 2013;368:503–12.CrossRefGoogle Scholar
  23. 23.
    Mohty D, Pibarot P, Despres JP, Cote C, Arsenault B, Cartier A, et al. Association between plasma LDL particle size, valvular accumulation of oxidized LDL, and inflammation in patients with aortic stenosis. Arterioscler Thromb Vasc Biol. 2008;28:187–93.CrossRefGoogle Scholar
  24. 24.
    Miller JD, Chu Y, Brooks RM, Richenbacher WE, Pena-Silva R, Heistad DD. Dysregulation of antioxidant mechanisms contributes to increased oxidative stress in calcific aortic valvular stenosis in humans. J Am Coll Cardiol. 2008;52:843–50.CrossRefGoogle Scholar
  25. 25.
    Lassegue B, Griendling KK. NADPH oxidases: functions and pathologies in the vasculature. Arterioscler Thromb Vasc Biol. 2010;3:653–61.CrossRefGoogle Scholar
  26. 26.
    Derbali H, Bosse Y, Cote N, Pibarot P, Audet A, Pepin A, et al. Increased biglycan in aortic valve stenosis leads to the overexpression of phospholipid transfer protein via Toll-like receptor 2. Am J Pathol. 2010;176:2638–45.CrossRefGoogle Scholar
  27. 27.
    Mahmut A, Boulanger MC, Fournier D, Couture C, Trahan S, Page S, et al. Lipoprotein lipase in aortic valve stenosis is associated with lipid retention and remodelling. Eur J Clin Investig. 2013;43:570–8.CrossRefGoogle Scholar
  28. 28.
    Mahmut A, Boulanger MC, El HD, Fournier D, Bouchareb R, Despres JP, et al. Elevated expression of lipoprotein-associated phospholipase A2 in calcific aortic valve disease: implications for valve mineralization. J Am Coll Cardiol. 2014;63:460–9.CrossRefGoogle Scholar
  29. 29.
    Bouchareb R, Mahmut A, Nsaibia MJ, Boulanger MC, Dahou A, Lepine JL, et al. Autotaxin derived from lipoprotein(a) and valve interstitial cells promotes inflammation and mineralization of the aortic valve. Circulation. 2015;132:677–90.CrossRefGoogle Scholar
  30. 30.
    Capoulade R, Mahmut A, Tastet L, Arsenault M, Bedard E, Dumesnil JG, et al. Impact of plasma Lp-PLA2 activity on the progression of aortic stenosis: the PROGRESSA study. JACC Cardiovasc Imaging. 2015;8:26–33.CrossRefGoogle Scholar
  31. 31.
    Mahmut A, Mahjoub H, Boulanger MC, Fournier D, Despres JP, Pibarot P, et al. Lp-PLA2 is associated with structural valve degeneration of bioprostheses. Eur J Clin Investig. 2014;44:136–45.CrossRefGoogle Scholar
  32. 32.
    Mahmut A, Mahjoub H, Boulanger MC, Dahou A, Bouchareb R, Capoulade R, et al. Circulating Lp-PLA2 is associated with high valvuloarterial impedance and low arterial compliance in patients with aortic valve bioprostheses. Clin Chim Acta. 2016;455:20–5.CrossRefGoogle Scholar
  33. 33.
    Nsaibia MJ, Mahmut A, Boulanger MC, Arsenault BJ, Bouchareb R, Simard S, et al. Autotaxin interacts with lipoprotein(a) and oxidized phospholipids in predicting the risk of calcific aortic valve stenosis in patients with coronary artery disease. J Intern Med. 2016;280:509–17.CrossRefGoogle Scholar
  34. 34.
    Mohty D, Pibarot P, Despres JP, Cartier A, Arsenault B, Picard F, et al. Age-related differences in the pathogenesis of calcific aortic stenosis: the potential role of resistin. Int J Cardiol. 2010;142:126–32.CrossRefGoogle Scholar
  35. 35.
    Guauque-Olarte S, Droit A, Tremblay-Marchand J, Gaudreault N, Kalavrouziotis D, Dagenais F, et al. RNA expression profile of calcified bicuspid, tricuspid and normal human aortic valves by RNA sequencing. Physiol Genomics. 2016;48:749–61.CrossRefGoogle Scholar
  36. 36.
    Charest A, Pepin A, Shetty R, Cote C, Voisine P, Dagenais F, et al. Distribution of SPARC during neovascularisation of degenerative aortic stenosis. Heart. 2006;92:1844–9.CrossRefGoogle Scholar
  37. 37.
    Yoshioka M, Yuasa S, Matsumura K, Kimura K, Shiomi T, Kimura N, et al. Chondromodulin-I maintains cardiac valvular function by preventing angiogenesis. Nat Med. 2006;12:1151–9.CrossRefGoogle Scholar
  38. 38.
    Isoda K, Matsuki T, Kondo H, Iwakura Y, Ohsuzu F. Deficiency of interleukin-1 receptor antagonist induces aortic valve disease in BALB/c mice. Arterioscler Thromb Vasc Biol. 2010;30:708–15.CrossRefGoogle Scholar
  39. 39.
    Lee HL, Woo KM, Ryoo HM, Baek JH. Tumor necrosis factor-alpha increases alkaline phosphatase expression in vascular smooth muscle cells via MSX2 induction. Biochem Biophys Res Commun. 2010;391:1087–92.CrossRefGoogle Scholar
  40. 40.
    Galeone A, Brunetti G, Oranger A, Greco G, Di BA, Mori G, et al. Aortic valvular interstitial cells apoptosis and calcification are mediated by TNF-related apoptosis-inducing ligand. Int J Cardiol. 2013;169:296–304.CrossRefGoogle Scholar
  41. 41.
    Kaden JJ, Bickelhaupt S, Grobholz R, Haase KK, Sarikoc A, Kilic R, et al. Receptor activator of nuclear factor kappaB ligand and osteoprotegerin regulate aortic valve calcification. J Mol Cell Cardiol. 2004;36:57–66.CrossRefGoogle Scholar
  42. 42.
    Weiss RM, Lund DD, Chu Y, Brooks RM, Zimmerman KA, El AR, et al. Osteoprotegerin inhibits aortic valve calcification and preserves valve function in hypercholesterolemic mice. PLoS One. 2013;8:e65201.CrossRefGoogle Scholar
  43. 43.
    El Husseini D, Boulanger MC, Mahmut A, Bouchareb R, Laflamme MH, Fournier D, et al. P2Y2 receptor represses IL-6 expression by valve interstitial cells through Akt: implication for calcific aortic valve disease. J Mol Cell Cardiol. 2014;72:146–56.CrossRefGoogle Scholar
  44. 44.
    Zeng Q, Song R, Ao L, Xu D, Venardos N, Fullerton DA, et al. Augmented osteogenic responses in human aortic valve cells exposed to oxLDL and TLR4 agonist: a mechanistic role of Notch1 and NF-kappaB interaction. PLoS One. 2014;9:e95400.CrossRefGoogle Scholar
  45. 45.
    Mathieu P, Bouchareb R, Boulanger MC. Innate and adaptive immunity in calcific aortic valve disease. J Immunol Res. 2015;2015:851945.CrossRefGoogle Scholar
  46. 46.
    Capoulade R, Clavel MA, Dumesnil JG, Chan KL, Teo KK, Tam JW, et al. Impact of metabolic syndrome on progression of aortic stenosis: influence of age and statin therapy. J Am Coll Cardiol. 2012;60:216–23.CrossRefGoogle Scholar
  47. 47.
    Cote N, Pibarot P, Pepin A, Fournier D, Audet A, Arsenault B, et al. Oxidized low-density lipoprotein, angiotensin II and increased waist circumference are associated with valve inflammation in prehypertensive patients with aortic stenosis. Int J Cardiol. 2010;145:444–9.CrossRefGoogle Scholar
  48. 48.
    Fujisaka T, Hoshiga M, Hotchi J, Takeda Y, Jin D, Takai S, et al. Angiotensin II promotes aortic valve thickening independent of elevated blood pressure in apolipoprotein-E deficient mice. Atherosclerosis. 2013;226:82–7.CrossRefGoogle Scholar
  49. 49.
    O'Brien KD, Shavelle DM, Caulfield MT, McDonald TO, Olin-Lewis K, Otto CM, et al. Association of angiotensin-converting enzyme with low-density lipoprotein in aortic valvular lesions and in human plasma. Circulation. 2002;106:2224–30.CrossRefGoogle Scholar
  50. 50.
    Helske S, Lindstedt KA, Laine M, Mayranpaa M, Werkkala K, Lommi J, et al. Induction of local angiotensin II-producing systems in stenotic aortic valves. J Am Coll Cardiol. 2004;44:1859–66.CrossRefGoogle Scholar
  51. 51.
    Cote N, Mahmut A, Fournier D, Boulanger MC, Couture C, Despres JP, et al. Angiotensin receptor blockers are associated with reduced fibrosis and interleukin-6 expression in calcific aortic valve disease. Pathobiology. 2014;81:15–24.CrossRefGoogle Scholar
  52. 52.
    Arishiro K, Hoshiga M, Negoro N, Jin D, Takai S, Miyazaki M, et al. Angiotensin receptor-1 blocker inhibits atherosclerotic changes and endothelial disruption of the aortic valve in hypercholesterolemic rabbits. J Am Coll Cardiol. 2007;49:1482–9.CrossRefGoogle Scholar
  53. 53.
    Bertazzo S, Gentleman E, Cloyd KL, Chester AH, Yacoub MH, Stevens MM. Nano-analytical electron microscopy reveals fundamental insights into human cardiovascular tissue calcification. Nat Mater. 2013;12:576–83.CrossRefGoogle Scholar
  54. 54.
    Bouchareb R, Boulanger MC, Fournier D, Pibarot P, Messaddeq Y, Mathieu P. Mechanical strain induces the production of spheroid mineralized microparticles in the aortic valve through a RhoA/ROCK-dependent mechanism. J Mol Cell Cardiol. 2014;67:49–59.CrossRefGoogle Scholar
  55. 55.
    Mathieu P. Pharmacology of ectonucleotidases: relevance for the treatment of cardiovascular disorders. Eur J Pharmacol. 2012;696:1–4.CrossRefGoogle Scholar
  56. 56.
    Cote N, El Husseini D, Pepin A, Guauque-Olarte S, Ducharme V, Bouchard-Cannon P, et al. ATP acts as a survival signal and prevents the mineralization of aortic valve. J Mol Cell Cardiol. 2012;52:1191–202.CrossRefGoogle Scholar
  57. 57.
    Mahmut A, Boulanger MC, Bouchareb R, Hadji F, Mathieu P. Adenosine derived from ecto-nucleotidases in calcific aortic valve disease promotes mineralization through A2a adenosine receptor. Cardiovasc Res. 2015;106:109–20.CrossRefGoogle Scholar
  58. 58.
    Mathieu P, Voisine P, Pepin A, Shetty R, Savard N, Dagenais F. Calcification of human valve interstitial cells is dependent on alkaline phosphatase activity. J Heart Valve Dis. 2005;14:353–7.PubMedGoogle Scholar
  59. 59.
    Bouchareb R, Cote N, Marie CB, Le Quang K, El Huseini D, Asselin J, et al. Carbonic anhydrase XII in valve interstitial cells promotes the regression of calcific aortic valve stenosis. J Mol Cell Cardiol. 2015;82:104–15.CrossRefGoogle Scholar
  60. 60.
    Asselin J, Roy C, Boudreau D, Messaddeq Y, Bouchareb R, Mathieu P. Supported core-shell nanobiosensors for quantitative fluorescence imaging of extracellular pH. Chem Commun (Camb). 2014;50:13746–9.CrossRefGoogle Scholar
  61. 61.
    Garg V, Muth AN, Ransom JF, Schluterman MK, Barnes R, King IN, et al. Mutations in NOTCH1 cause aortic valve disease. Nature. 2005;437:270–4.CrossRefGoogle Scholar
  62. 62.
    Ducharme V, Guauque-Olarte S, Gaudreault N, Pibarot P, Mathieu P, Bosse Y. NOTCH1 genetic variants in patients with tricuspid calcific aortic valve stenosis. J Heart Valve Dis. 2013;22:142–9.PubMedGoogle Scholar
  63. 63.
    Caira FC, Stock SR, Gleason TG, McGee EC, Huang J, Bonow RO, et al. Human degenerative valve disease is associated with up-regulation of low-density lipoprotein receptor-related protein 5 receptor-mediated bone formation. J Am Coll Cardiol. 2006;47:1707–12.CrossRefGoogle Scholar
  64. 64.
    Michelena HI, Prakash SK, Della CA, Bissell MM, Anavekar N, Mathieu P, et al. Bicuspid aortic valve: identifying knowledge gaps and rising to the challenge from the International Bicuspid Aortic Valve Consortium (BAVCon). Circulation. 2014;129:2691–704.CrossRefGoogle Scholar
  65. 65.
    Unger P, Clavel MA, Lindman BR, Mathieu P, Pibarot P. Pathophysiology and management of multivalvular disease. Nat Rev Cardiol. 2016;13:429–40.CrossRefGoogle Scholar
  66. 66.
    Hinton RB Jr, Lincoln J, Deutsch GH, Osinska H, Manning PB, Benson DW, et al. Extracellular matrix remodeling and organization in developing and diseased aortic valves. Circ Res. 2006;98:1431–8.CrossRefGoogle Scholar
  67. 67.
    Padang R, Bagnall RD, Richmond DR, Bannon PG, Semsarian C. Rare non-synonymous variations in the transcriptional activation domains of GATA5 in bicuspid aortic valve disease. J Mol Cell Cardiol. 2012;53:277–81.CrossRefGoogle Scholar
  68. 68.
    Laforest B, Andelfinger G, Nemer M. Loss of Gata5 in mice leads to bicuspid aortic valve. J Clin Invest. 2011;121:2876–87.CrossRefGoogle Scholar
  69. 69.
    Jain R, Engleka KA, Rentschler SL, Manderfield LJ, Li L, Yuan L, et al. Cardiac neural crest orchestrates remodeling and functional maturation of mouse semilunar valves. J Clin Invest. 2011;121:422–30.CrossRefGoogle Scholar
  70. 70.
    Cotrufo M, Della CA, De Santo LS, Quarto C, De FM, Romano G, et al. Different patterns of extracellular matrix protein expression in the convexity and the concavity of the dilated aorta with bicuspid aortic valve: preliminary results. J Thorac Cardiovasc Surg. 2005;130:504–11.CrossRefGoogle Scholar
  71. 71.
    Mathieu P, Boulanger MC, Bouchareb R. Molecular biology of calcific aortic valve disease: towards new pharmacological therapies. Expert Rev Cardiovasc Ther. 2014;12:851–62.CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Austria, part of Springer Nature 2019

Authors and Affiliations

  • Ghada Mkannez
    • 1
  • Deborah Argaud
    • 1
  • Marie-Chloé Boulanger
    • 1
  • Patrick Mathieu
    • 1
    • 2
    Email author
  1. 1.Department of Surgery, Laboratory of Cardiovascular Pathobiology, Quebec Heart and Lung Institute/Research CenterLaval UniversityQuébecCanada
  2. 2.Institut de Cardiologie et de Pneumologie de QuébecQuebec Heart and Lung InstituteQCCanada

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