Valve interstitial cells: The key to understanding the pathophysiology of heart valve calcification

Journal of the American Heart Association

Volumn 6, Issue 9, 2017, Pages

  Rutkovskiy, Arkady ^a,b,c,f   Malashicheva, Anna ^d,f   Sullivan, Gareth ^a,b,e   Bogdanova, Maria ^a   Kostareva, Anna ^d,f   Stensløkken, Kåre Olav ^a   Fiane, Arnt ^a,b   Vaage, Jarle ^a,b,f  

^a UNIVERSITY OF OSLO   (Norway)

^b OSLO UNIVERSITY HOSPITAL   (Norway)

^c AKERSHUS UNIVERSITY HOSPITAL   (Norway)

^d ALMAZOV NATIONAL MEDICAL RESEARCH CENTRE   (Russian Federation)

^e Norwegian Center for Stem Cell Research   (Norway)

^f ITMO UNIVERSITY   (Russian Federation)

Author keywords

[No Author keywords available]

Indexed keywords

ALPHA SMOOTH MUSCLE ACTIN; ATORVASTATIN; BIGLYCAN; CYCLOOXYGENASE 2; HEAT SHOCK PROTEIN 47; HIGH MOBILITY GROUP B1 PROTEIN; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; INTERCELLULAR ADHESION MOLECULE 1; INTERLEUKIN 6; MICRORNA; NOTCH RECEPTOR; OXIDIZED LOW DENSITY LIPOPROTEIN; PRAVASTATIN; SIMVASTATIN; WNT PROTEIN; AUTACOID;

AORTIC VALVE STENOSIS; ARTICLE; ATHEROSCLEROSIS; CALCIFICATION; CARDIAC MUSCLE CELL; CELL DIFFERENTIATION; CELL ISOLATION; DISEASE MODEL; DRUG EFFECT; ENDOTHELIUM CELL; EPIGENETICS; HEART VALVE CALCIFICATION; HUMAN; INFLAMMATION; MECHANICAL STRESS; MOLECULAR INTERACTION; MYOFIBROBLAST; NONHUMAN; OSTEOBLAST; PATHOPHYSIOLOGY; PRIORITY JOURNAL; PROTEIN EXPRESSION; SEX DIFFERENCE; VALVE INTERSTITIAL CELL; VALVULAR HEART DISEASE; ANIMAL; AORTIC VALVE; BONE DEVELOPMENT; CALCINOSIS; CELL CULTURE; CELL SEPARATION; FIBROBLAST; GENETICS; HEMODYNAMICS; METABOLISM; PATHOLOGY; PHENOTYPE; PROCEDURES; SIGNAL TRANSDUCTION;

ANIMALS; AORTIC VALVE; AORTIC VALVE STENOSIS; CALCINOSIS; CELL DIFFERENTIATION; CELL SEPARATION; CELLS, CULTURED; FIBROBLASTS; HEMODYNAMICS; HUMANS; INFLAMMATION MEDIATORS; MICRORNAS; MYOFIBROBLASTS; OSTEOBLASTS; OSTEOGENESIS; PHENOTYPE; SIGNAL TRANSDUCTION;

EID: 85029746981     PISSN: None     EISSN: 20479980     Source Type: Journal    
DOI: 10.1161/JAHA.117.006339     Document Type: Article

References (133)

1. Iung B, Baron G, Butchart EG, Delahaye F, Gohlke-Bärwolf C, Levang OW, Tornos P, Vanoverschelde J-L, Vermeer F, Boersma E. A prospective survey of patients with valvular heart disease in Europe: the Euro Heart Survey on Valvular Heart Disease. Eur Heart J. 2003;24:1231-1243
2. O'Brien KD. Epidemiology and genetics of calcific aortic valve disease. J Investig Med. 2007;55:284-291
3. Goldbarg SH, Elmariah S, Miller MA, Fuster V. Insights into degenerative aortic valve disease. J Am Coll Cardiol. 2007;50:1205-1213
4. Pomerance A. Ageing changes in human heart valves. Br Heart J. 1967;29:222-231
5. Misfeld M, Sievers HH. Heart valve macro-and microstructure. Philos Trans R Soc Lond B Biol Sci. 2007;362:1421-1436
6. Helske S, Kupari M, Lindstedt KA, Kovanen PT. Aortic valve stenosis: an active atheroinflammatory process. Curr Opin Lipidol. 2007;18:483-491
7. Butcher JT, Markwald RR. Valvulogenesis: the moving target. Philos Trans R Soc Lond B Biol Sci. 2007;362:1489-1503
8. Mohler ER III. Mechanisms of aortic valve calcification. Am J Cardiol. 2004;94:1396-1402, A1396
9. Chen JH, Simmons CA. Cell-matrix interactions in the pathobiology of calcific aortic valve disease: critical roles for matricellular, matricrine, and matrix mechanics cues. Circ Res. 2011;108:1510-1524
10. Cawley PJ, Otto CM. Prevention of calcific aortic valve stenosis-fact or fiction? Ann Med. 2009;41:100-108
11. Zigelman CZ, Edelstein PM. Aortic valve stenosis. Anesthesiol Clin. 2009;27:519-532
12. Akat K, Borggrefe M, Kaden JJ. Aortic valve calcification: basic science to clinical practice. Heart. 2009;95:616-623
13. Babu AN, Meng X, Zou N, Yang X, Wang M, Song Y, Cleveland JC, Weyant M, Banerjee A, Fullerton DA. Lipopolysaccharide stimulation of human aortic valve interstitial cells activates inflammation and osteogenesis. Ann Thorac Surg. 2008;86:71-76
14. Xu S, Liu AC, Gotlieb AI. Common pathogenic features of atherosclerosis and calcific aortic stenosis: role of transforming growth factor-β. Cardiovasc Pathol. 2010;19:236-247
15. Farzaneh-Far A, Proudfoot D, Shanahan C, Weissberg PL. Vascular and valvar calcification: recent advances. Heart. 2001;85:13-17
16. Miller JD, Weiss RM, Heistad DD. Calcific aortic valve stenosis: methods, models, and mechanisms. Circ Res. 2011;108:1392-1412
17. Butcher JT, Nerem RM. Valvular endothelial cells regulate the phenotype of interstitial cells in co-culture: effects of steady shear stress. Tissue Eng. 2006;12:905-915
18. Bond WS, Roberts EL, Warnock JN. Evaluation of porcine aortic valve interstitial cell activity using different serum types in two-and threedimensional culture. Tissue Eng. 2007;13:343-349
19. Jian B, Xu J, Connolly J, Savani RC, Narula N, Liang B, Levy RJ. Serotonin mechanisms in heart valve disease I: serotonin-induced up-regulation of transforming growth factor-β1 via G-protein signal transduction in aortic valve interstitial cells. Am J Pathol. 2002;161:2111-2121
20. Merryman WD, Youn I, Lukoff HD, Krueger PM, Guilak F, Hopkins RA, Sacks MS. Correlation between heart valve interstitial cell stiffness and transvalvular pressure: implications for collagen biosynthesis. Am J Physiol Heart Circ Physiol. 2006;290:H224-H231
21. Gwanmesia P, Ziegler H, Eurich R, Barth M, Kamiya H, Karck M, Lichtenberg A, Akhyari P. Opposite effects of transforming growth factor-β1 and vascular endothelial growth factor on the degeneration of aortic valvular interstitial cell are modified by the extracellular matrix protein fibronectin: implications for heart valve engineering. Tissue Eng Part A. 2010;16:3737-3746
22. Rattazzi M, Iop L, Faggin E, Bertacco E, Zoppellaro G, Baesso I, Puato M, Torregrossa G, Fadini GP, Agostini C, Gerosa G, Sartore S, Pauletto P. Clones of interstitial cells from bovine aortic valve exhibit different calcifying potential when exposed to endotoxin and phosphate. Arterioscler Thromb Vasc Biol. 2008;28:2165-2172
23. Renato M, Bertacco E, Franchin C, Arrigoni G, Rattazzi M. Proteomic analysis of interstitial aortic valve cells acquiring a pro-calcific profile. Methods Mol Biol. 2013;1005:95-107
24. Duan B, Hockaday LA, Kapetanovic E, Kang KH, Butcher JT. Stiffness and adhesivity control aortic valve interstitial cell behavior within hyaluronic acid based hydrogels. Acta Biomater. 2013;9:7640-7650
25. El Husseini D, Boulanger MC, Mahmut A, Bouchareb R, Laflamme MH, Fournier D, Pibarot P, Bosse Y, Mathieu P. P2Y2 receptor represses IL-6 expression by valve interstitial cells through Akt: implication for calcific aortic valve disease. J Mol Cell Cardiol. 2014;72:146-156
26. Yip CY, Blaser MC, Mirzaei Z, Zhong X, Simmons CA. Inhibition of pathological differentiation of valvular interstitial cells by C-type natriuretic peptide. Arterioscler Thromb Vasc Biol. 2011;31:1881-1889
27. Roberts WC, Ko JM. Frequency by decades of unicuspid, bicuspid, and tricuspid aortic valves in adults having isolated aortic valve replacement for aortic stenosis, with or without associated aortic regurgitation. Circulation. 2005;111:920-925
28. Garg V. Molecular genetics of aortic valve disease. Curr Opin Cardiol. 2006;21:180-184
29. McCoy CM, Nicholas DQ, Masters KS. Sex-related differences in gene expression by porcine aortic valvular interstitial cells. PLoS One. 2012;7: e39980
30. Yang X, Fullerton DA, Su X, Ao L, Cleveland JC Jr, Meng X. Pro-osteogenic phenotype of human aortic valve interstitial cells is associated with higher levels of toll-like receptors 2 and 4 and enhanced expression of bone morphogenetic protein 2. J Am Coll Cardiol. 2009;53:491-500
31. Ferdous Z, Jo H, Nerem RM. Differences in valvular and vascular cell responses to strain in osteogenic media. Biomaterials. 2011;32:2885-2893
32. Osman L, Yacoub MH, Latif N, Amrani M, Chester AH. Role of human valve interstitial cells in valve calcification and their response to atorvastatin. Circulation. 2006;114:I547-I552
33. Meng X, Ao L, Song Y, Babu A, Yang X, Wang M, Weyant MJ, Dinarello CA, Cleveland JC Jr, Fullerton DA. Expression of functional toll-like receptors 2 and 4 in human aortic valve interstitial cells: potential roles in aortic valve inflammation and stenosis. Am J Physiol. 2008;294:C29-C35
34. Nadlonek N, Lee JH, Reece TB, Weyant MJ, Cleveland JC Jr, Meng X, Fullerton DA. Interleukin-1 beta induces an inflammatory phenotype in human aortic valve interstitial cells through nuclear factor kappa beta. Ann Thorac Surg. 2013;96:155-162
35. Yu Z, Seya K, Daitoku K, Motomura S, Fukuda I, Furukawa K. Tumor necrosis factor-a accelerates the calcification of human aortic valve interstitial cells obtained from patients with calcific aortic valve stenosis via the BMP2-Dlx5 pathway. J Pharmacol Exp Ther. 2011;337:16-23
36. Jian B, Jones PL, Li Q, Mohler ER III, Schoen FJ, Levy RJ. Matrix metalloproteinase-2 is associated with tenascin-C in calcific aortic stenosis. Am J Pathol. 2001;159:321-327
37. Wang B, Li F, Zhang C, Wei G, Liao P, Dong N. High-mobility group box-1 protein induces osteogenic phenotype changes in aortic valve interstitial cells. J Thorac Cardiovasc Surg. 2016;151:255-262
38. Clark-Greuel JN, Connolly JM, Sorichillo E, Narula NR, Rapoport HS, Mohler ER III, Gorman JH III, Gorman RC, Levy RJ. Transforming growth factor-β1 mechanisms in aortic valve calcification: increased alkaline phosphatase and related events. Ann Thorac Surg. 2007;83:946-953
39. Zhang M, Liu X, Zhang X, Song Z, Han L, He Y, Xu Z. MicroRNA-30b is a multifunctional regulator of aortic valve interstitial cells. J Thorac Cardiovasc Surg. 2014;147:1073-1080.e1072
40. Osman L, Chester AH, Sarathchandra P, Latif N, Meng W, Taylor PM, Yacoub MH. A novel role of the sympatho-adrenergic system in regulating valve calcification. Circulation. 2007;116:I282-I287
41. Olsson M, Rosenqvist M, Nilsson J. Expression of HLA-DR antigen and smooth muscle cell differentiation markers by valvular fibroblasts in degenerative aortic stenosis. J Am Coll Cardiol. 1994;24:1664-1671
42. Osman N, Grande-Allen KJ, Ballinger ML, Getachew R, Marasco S, O'Brien KD, Little PJ. Smad2-dependent glycosaminoglycan elongation in aortic valve interstitial cells enhances binding of LDL to proteoglycans. Cardiovasc Pathol. 2013;22:146-155
43. Wang H, Sridhar B, Leinwand LA, Anseth KS. Characterization of cell subpopulations expressing progenitor cell markers in porcine cardiac valves. PLoS One. 2013;8:e69667
44. Cimini M, Rogers KA, Boughner DR. Smoothelin-positive cells in human and porcine semilunar valves. Histochem Cell Biol. 2003;120:307-317
45. Ku CH, Johnson PH, Batten P, Sarathchandra P, Chambers RC, Taylor PM, Yacoub MH, Chester AH. Collagen synthesis by mesenchymal stem cells and aortic valve interstitial cells in response to mechanical stretch. Cardiovasc Res. 2006;71:548-556
46. Pho M, Lee W, Watt DR, Laschinger C, Simmons CA, McCulloch CA. Cofilin is a marker of myofibroblast differentiation in cells from porcine aortic cardiac valves. Am J Physiol Heart Circ Physiol. 2008;294:H1767-H1778
47. Messier RH Jr, Bass BL, Aly HM, Jones JL, Domkowski PW, Wallace RB, Hopkins RA. Dual structural and functional phenotypes of the porcine aortic valve interstitial population: characteristics of the leaflet myofibroblast. J Surg Res. 1994;57:1-21
48. Gu X, Masters KS. Regulation of valvular interstitial cell calcification by adhesive peptide sequences. J Biomed Mater Res A. 2010;93:1620-1630
49. Latif N, Quillon A, Sarathchandra P, McCormack A, Lozanoski A, Yacoub MH, Chester AH. Modulation of human valve interstitial cell phenotype and function using a fibroblast growth factor 2 formulation. PLoS One. 2015;10: e0127844
50. Poggio P, Sainger R, Branchetti E, Grau JB, Lai EK, Gorman RC, Sacks MS, Parolari A, Bavaria JE, Ferrari G. Noggin attenuates the osteogenic activation of human valve interstitial cells in aortic valve sclerosis. Cardiovasc Res. 2013;98:402-410
51. Warnock JN, Nanduri B, Pregonero GAMEZ CA, Tang J, Koback D, Muir WM, Burgess SC. Gene profiling of aortic valve interstitial cells under elevated pressure conditions: modulation of inflammatory gene networks. Int J Inflamm. 2011;2011:176412
52. Witt W, Jannasch A, Burkhard D, Christ T, Ravens U, Brunssen C, Leuner A, Morawietz H, Matschke K, Waldow T. Sphingosine-1-phosphate induces contraction of valvular interstitial cells from porcine aortic valves. Cardiovasc Res. 2012;93:490-497
53. Merryman WD, Liao J, Parekh A, Candiello JE, Lin H, Sacks MS. Differences in tissue-remodeling potential of aortic and pulmonary heart valve interstitial cells. Tissue Eng. 2007;13:2281-2289
54. Benton JA, Kern HB, Anseth KS. Substrate properties influence calcification in valvular interstitial cell culture. J Heart Valve Dis. 2008;17:689-699
55. Yip CY, Chen JH, Zhao R, Simmons CA. Calcification by valve interstitial cells is regulated by the stiffness of the extracellular matrix. Arterioscler Thromb Vasc Biol. 2009;29:936-942
56. Benton JA, Kern HB, Leinwand LA, Mariner PD, Anseth KS. Statins block calcific nodule formation of valvular interstitial cells by inhibiting a-smooth muscle actin expression. Arterioscler Thromb Vasc Biol. 2009;29:1950-1957
57. Hakuno D, Kimura N, Yoshioka M, Mukai M, Kimura T, Okada Y, Yozu R, Shukunami C, Hiraki Y, Kudo A, Ogawa S, Fukuda K. Periostin advances atherosclerotic and rheumatic cardiac valve degeneration by inducing angiogenesis and MMP production in humans and rodents. J Clin Invest. 2010;120:2292-2306
58. Bertacco E, Millioni R, Arrigoni G, Faggin E, Iop L, Puato M, Pinna LA, Tessari P, Pauletto P, Rattazzi M. Proteomic analysis of clonal interstitial aortic valve cells acquiring a pro-calcific profile. J Proteome Res. 2010;9:5913-5921
59. Rodriguez KJ, Piechura LM, Masters KS. Regulation of valvular interstitial cell phenotype and function by hyaluronic acid in 2-D and 3-D culture environments. Matrix Biol. 2011;30:70-82
60. Hutcheson JD, Venkataraman R, Baudenbacher FJ, Merryman WD. Intracellular Ca(2+) accumulation is strain-dependent and correlates with apoptosis in aortic valve fibroblasts. J Biomech. 2012;45:888-894
61. Wyss K, Yip CY, Mirzaei Z, Jin X, Chen JH, Simmons CA. The elastic properties of valve interstitial cells undergoing pathological differentiation. J Biomech. 2012;45:882-887
62. Gould RA, Chin K, Santisakultarm TP, Dropkin A, Richards JM, Schaffer CB, Butcher JT. Cyclic strain anisotropy regulates valvular interstitial cell phenotype and tissue remodeling in three-dimensional culture. Acta Biomater. 2012;8:1710-1719
63. Fisher CI, Chen J, Merryman WD. Calcific nodule morphogenesis by heart valve interstitial cells is strain dependent. Biomech Model Mechanobiol. 2013;12:5-17
64. Quinlan AM, Billiar KL. Investigating the role of substrate stiffness in the persistence of valvular interstitial cell activation. J Biomed Mater Res A. 2012;100:2474-2482
65. Monzack EL, Masters KS. A time course investigation of the statin paradox among valvular interstitial cell phenotypes. Am J Physiol Heart Circ Physiol. 2012;303:H903-H909
66. Moraes C, Likhitpanichkul M, Lam CJ, Beca BM, Sun Y, Simmons CA. Microdevice array-based identification of distinct mechanobiological response profiles in layer-specific valve interstitial cells. Integr Biol (Camb). 2013;5:673-680
67. Richards J, El-Hamamsy I, Chen S, Sarang Z, Sarathchandra P, Yacoub MH, Chester AH, Butcher JT. Side-specific endothelial-dependent regulation of aortic valve calcification: interplay of hemodynamics and nitric oxide signaling. Am J Pathol. 2013;182:1922-1931
68. Ferdous Z, Jo H, Nerem RM. Strain magnitude-dependent calcific marker expression in valvular and vascular cells. Cells Tissues Organs. 2013;197:372-383
69. Gould ST, Matherly EE, Smith JN, Heistad DD, Anseth KS. The role of valvular endothelial cell paracrine signaling and matrix elasticity on valvular interstitial cell activation. Biomaterials. 2014;35:3596-3606
70. Porras AM, van Engeland NC, Marchbanks E, McCormack A, Bouten CV, Yacoub MH, Latif N, Masters KS. Robust generation of quiescent porcine valvular interstitial cell cultures. J Am Heart Assoc. 2017;6:e005041. DOI: 10. 1161/JAHA.116.005041
71. Osman L, Chester AH, Amrani M, Yacoub MH, Smolenski RT. A novel role of extracellular nucleotides in valve calcification: a potential target for atorvastatin. Circulation. 2006;114:I566-I572
72. Farrar EJ, Butcher JT. Heterogeneous susceptibility of valve endothelial cells to mesenchymal transformation in response to TNFα. Ann Biomed Eng. 2014;42:149-161
73. 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;174:1109-1119
74. Venardos N, Nadlonek NA, Zhan Q, Weyant MJ, Reece TB, Meng X, Fullerton DA. Aortic valve calcification is mediated by a differential response of aortic valve interstitial cells to inflammation. J Surg Res. 2014;190:1-8
75. Dreger SA, Thomas P, Sachlos E, Chester AH, Czernuszka JT, Taylor PM, Yacoub MH. Potential for synthesis and degradation of extracellular matrix proteins by valve interstitial cells seeded onto collagen scaffolds. Tissue Eng. 2006;12:2533-2540
76. Cushing MC, Mariner PD, Liao JT, Sims EA, Anseth KS. Fibroblast growth factor represses Smad-mediated myofibroblast activation in aortic valvular interstitial cells. FASEB J. 2008;22:1769-1777
77. Sapp MC, Fares HJ, Estrada AC, Grande-Allen KJ. Multilayer three-dimensional filter paper constructs for the culture and analysis of aortic valvular interstitial cells. Acta Biomater. 2015;13:199-206
78. Mabry KM, Lawrence RL, Anseth KS. Dynamic stiffening of poly(ethylene glycol)-based hydrogels to direct valvular interstitial cell phenotype in a threedimensional environment. Biomaterials. 2015;49:47-56
79. Hutcheson JD, Chen J, Sewell-Loftin MK, Ryzhova LM, Fisher CI, Su YR, Merryman WD. Cadherin-11 regulates cell-cell tension necessary for calcific nodule formation by valvular myofibroblasts. Arterioscler Thromb Vasc Biol. 2013;33:114-120
80. Monzack EL, Gu X, Masters KS. Efficacy of simvastatin treatment of valvular interstitial cells varies with the extracellular environment. Arterioscler Thromb Vasc Biol. 2009;29:246-253
81. Kennedy JA, Hua X, Mishra K, Murphy GA, Rosenkranz AC, Horowitz JD. Inhibition of calcifying nodule formation in cultured porcine aortic valve cells by nitric oxide donors. Eur J Pharmacol. 2009;602:28-35
82. Hutcheson JD, Ryzhova LM, Setola V, Merryman WD. 5-HT(2B) antagonism arrests non-canonical TGF-β1-induced valvular myofibroblast differentiation. J Mol Cell Cardiol. 2012;53:707-714
83. Monzack EL, Masters KS. Can valvular interstitial cells become true osteoblasts? A side-by-side comparison. J Heart Valve Dis. 2011;20:449-463
84. Cloyd KL, El-Hamamsy I, Boonrungsiman S, Hedegaard M, Gentleman E, Sarathchandra P, Colazzo F, Gentleman MM, Yacoub MH, Chester AH, Stevens MM. Characterization of porcine aortic valvular interstitial cell 'calcified' nodules. PLoS One. 2012;7:e48154
85. Lehmann S, Walther T, Kempfert J, Rastan A, Garbade J, Dhein S, Mohr FW. Mechanical strain and the aortic valve: influence on fibroblasts, extracellular matrix, and potential stenosis. Ann Thorac Surg. 2009;88:1476-1483
86. Yan YX, Gong YW, Guo Y, Lv Q, Guo C, Zhuang Y, Zhang Y, Li R, Zhang XZ. Mechanical strain regulates osteoblast proliferation through integrinmediated ERK activation. PLoS One. 2012;7:e35709
87. Boppart MD, Kimmel DB, Yee JA, Cullen DM. Time course of osteoblast appearance after in vivo mechanical loading. Bone. 1998;23:409-415
88. Yang X, Meng X, Su X, Mauchley DC, Ao L, Cleveland JC Jr, Fullerton DA. Bone morphogenic protein 2 induces Runx2 and osteopontin expression in human aortic valve interstitial cells: role of Smad1 and extracellular signal-regulated kinase 1/2. J Thorac Cardiovasc Surg. 2009;138:1008-1015
89. Nigam V, Srivastava D. Notch1 represses osteogenic pathways in aortic valve cells. J Mol Cell Cardiol. 2009;47:828-834
90. Chen JH, Chen WL, Sider KL, Yip CY, Simmons CA.β-Catenin mediates mechanically regulated, transforming growth factor-β1-induced myofibroblast differentiation of aortic valve interstitial cells. Arterioscler Thromb Vasc Biol. 2011;31:590-597
91. Carthy JM, Boroomand S, McManus BM. Versican and CD44 in in vitro valvular interstitial cell injury and repair. Cardiovasc Pathol. 2012;21:74-82
92. Yanagawa B, Lovren F, Pan Y, Garg V, Quan A, Tang G, Singh KK, Shukla PC, Kalra NP, Peterson MD, Verma S. miRNA-141 is a novel regulator of BMP-2-mediated calcification in aortic stenosis. J Thorac Cardiovasc Surg. 2012;144:256-262
93. Xu S, Gotlieb AI. Wnt3α/β-catenin increases proliferation in heart valve interstitial cells. Cardiovasc Pathol. 2013;22:156-166
94. Song R, Zeng Q, Ao L, Yu JA, Cleveland JC, Zhao KS, Fullerton DA, Meng X. Biglycan induces the expression of osteogenic factors in human aortic valve interstitial cells via toll-like receptor-2. Arterioscler Thromb Vasc Biol. 2012;32:2711-2720
95. Zeng Q, Jin C, Ao L, Cleveland JC Jr, Song R, Xu D, Fullerton DA, Meng X. Cross-talk between the toll-like receptor 4 and Notch1 pathways augments the inflammatory response in the interstitial cells of stenotic human aortic valves. Circulation. 2012;126:S222-S230
96. Nadlonek NA, Weyant MJ, Yu JA, Cleveland JC Jr, Reece TB, Meng X, Fullerton DA. Radiation induces osteogenesis in human aortic valve interstitial cells. J Thorac Cardiovasc Surg. 2012;144:1466-1470
97. Branchetti E, Sainger R, Poggio P, Grau JB, Patterson-Fortin J, Bavaria JE, Chorny M, Lai E, Gorman RC, Levy RJ, Ferrari G. Antioxidant enzymes reduce DNA damage and early activation of valvular interstitial cells in aortic valve sclerosis. Arterioscler Thromb Vasc Biol. 2013;33:e66-e74
98. Zeng Q, Song R, Ao L, Weyant MJ, Lee J, Xu D, Fullerton DA, Meng X. Notch1 promotes the pro-osteogenic response of human aortic valve interstitial cells via modulation of ERK1/2 and nuclear factor-jB activation. Arterioscler Thromb Vasc Biol. 2013;33:1580-1590
99. Galeone A, Brunetti G, Oranger A, Greco G, Di Benedetto A, Mori G, Colucci S, Zallone A, Paparella D, Grano M. Aortic valvular interstitial cells apoptosis and calcification are mediated by TNF-related apoptosis-inducing ligand. Int J Cardiol. 2013;169:296-304
100. Zhang XW, Zhang BY, Wang SW, Gong DJ, Han L, Xu ZY, Liu XH. Twist-related protein 1 negatively regulated osteoblastic transdifferentiation of human aortic valve interstitial cells by directly inhibiting runt-related transcription factor 2. J Thorac Cardiovasc Surg. 2014;148:1700-1708.e1701
101. Carrion K, Dyo J, Patel V, Sasik R, Mohamed SA, Hardiman G, Nigam V. The long non-coding HOTAIR is modulated by cyclic stretch and WNT/β-CATENIN in human aortic valve cells and is a novel repressor of calcification genes. PLoS One. 2014;9:e96577
102. Zeng Q, Song R, Ao L, Xu D, Venardos N, Fullerton DA, Meng X. Augmented osteogenic responses in human aortic valve cells exposed to oxLDL and TLR4 agonist: a mechanistic role of Notch1 and NF-jB interaction. PLoS One. 2014;9:e95400
103. Witt W, Buttner P, Jannasch A, Matschke K, Waldow T. Reversal of myofibroblastic activation by polyunsaturated fatty acids in valvular interstitial cells from aortic valves. Role of RhoA/G-actin/MRTF signalling. J Mol Cell Cardiol. 2014;74C:127-138
104. Song R, Ao L, Zhao KS, Zheng D, Venardos N, Fullerton DA, Meng X. Soluble biglycan induces the production of ICAM-1 and MCP-1 in human aortic valve interstitial cells through TLR2/4 and the ERK1/2 pathway. Inflamm Res. 2014;63:703-710
105. Canalis E. Notch signaling in osteoblasts. Sci Signal. 2008;1:pe17
106. Gessert S, Kuhl M. The multiple phases and faces of Wnt signaling during cardiac differentiation and development. Circ Res. 2010;107:186-199
107. Hurlstone AF, Haramis AP, Wienholds E, Begthel H, Korving J, Van Eeden F, Cuppen E, Zivkovic D, Plasterk RH, Clevers H. The Wnt/β-catenin pathway regulates cardiac valve formation. Nature. 2003;425:633-637
108. Ozhan G, Weidinger G. Wnt/β-catenin signaling in heart regeneration. Cell Regen (Lond). 2015;4:3
109. Clevers H, Nusse R. Wnt/β-catenin signaling and disease. Cell. 2012;149:1192-1205
110. Yavropoulou MP, Yovos JG. The role of the Wnt signaling pathway in osteoblast commitment and differentiation. Hormones (Athens). 2007;6:279-294
111. Rajamannan NM, Subramaniam M, Caira F, Stock SR, Spelsberg TC. Atorvastatin inhibits hypercholesterolemia-induced calcification in the aortic valves via the Lrp5 receptor pathway. Circulation. 2005;112:I229-I234
112. Stewart BF, Siscovick D, Lind BK, Gardin JM, Gottdiener JS, Smith VE, Kitzman DW, Otto CM. Clinical factors associated with calcific aortic valve disease. Cardiovascular health study. J Am Coll Cardiol. 1997;29:630-634
113. Butcher JT, Mahler GJ, Hockaday LA. Aortic valve disease and treatment: the need for naturally engineered solutions. Adv Drug Deliv Rev. 2011;63:242-268
114. Andersson ER, Sandberg R, Lendahl U. Notch signaling: simplicity in design, versatility in function. Development. 2011;138:3593-3612
115. Garg V, Muth AN, Ransom JF, Schluterman MK, Barnes R, King IN, Grossfeld PD, Srivastava D. Mutations in Notch1 cause aortic valve disease. Nature. 2005;437:270-274
116. Deregowski V, Gazzerro E, Priest L, Rydziel S, Canalis E. Notch 1 overexpression inhibits osteoblastogenesis by suppressing Wnt/β-catenin but not bone morphogenetic protein signaling. J Biol Chem. 2006;281:6203-6210
117. Zhu F, Sweetwyne MT, Hankenson KD. PKCd is required for Jagged-1 induction of human mesenchymal stem cell osteogenic differentiation. Stem Cells. 2013;31:1181-1192
118. Chen J, Ryzhova LM, Sewell-Loftin MK, Brown CB, Huppert SS, Baldwin HS, Merryman WD. Notch1 mutation leads to valvular calcification through enhanced myofibroblast mechanotransduction. Arterioscler Thromb Vasc Biol. 2015;35:1597-1605
119. Acharya A, Hans CP, Koenig SN, Nichols HA, Galindo CL, Garner HR, Merrill WH, Hinton RB, Garg V. Inhibitory role of Notch1 in calcific aortic valve disease. PLoS One. 2011;6:e27743
120. El Accaoui RN, Gould ST, Hajj GP, Chu Y, Davis MK, Kraft DC, Lund DD, Brooks RM, Doshi H, Zimmerman KA, Kutschke W, Anseth KS, Heistad DD, Weiss RM. Aortic valve sclerosis in mice deficient in endothelial nitric oxide synthase. Am J Physiol Heart Circ Physiol. 2014;306:H1302-H1313
121. Hjortnaes J, Shapero K, Goettsch C, Hutcheson JD, Keegan J, Kluin J, Mayer JE, Bischoff J, Aikawa E. Valvular interstitial cells suppress calcification of valvular endothelial cells. Atherosclerosis. 2015;242:251-260
122. Wang Y, Wu B, Farrar E, Lui W, Lu P, Zhang D, Alfieri CM, Mao K, Chu M, Yang D, Xu D, Rauchman M, Taylor V, Conway SJ, Yutzey KE, Butcher JT, Zhou B. Notch-TNF signalling is required for development and homeostasis of arterial valves. Eur Heart J. 2017;38:675-686
123. Nadlonek NA, Lee JH, Weyant MJ, Meng X, Fullerton DA. Ox-LDL induces PiT-1 expression in human aortic valve interstitial cells. J Surg Res. 2013;184:6-9
124. Li F, Zhao Z, Cai Z, Dong N, Liu Y. Oxidized low-density lipoprotein promotes osteoblastic differentiation of valvular interstitial cells through RAGE/MAPK. Cardiology. 2015;130:55-61
125. Passmore M, Nataatmadja M, Fung YL, Pearse B, Gabriel S, Tesar P, Fraser JF. Osteopontin alters endothelial and valvular interstitial cell behaviour in calcific aortic valve stenosis through HMGB1 regulation. Eur J Cardiothorac Surg. 2015;48:e20-e29
126. Wang D, Zeng Q, Song R, Ao L, Fullerton DA, Meng X. Ligation of ICAM-1 on human aortic valve interstitial cells induces the osteogenic response: a critical role of the Notch1-NF-jB pathway in BMP-2 expression. Biochem Biophys Acta. 2014;1843:2744-2753
127. Kreke MR, Sharp LA, Lee YW, Goldstein AS. Effect of intermittent shear stress on mechanotransductive signaling and osteoblastic differentiation of bone marrow stromal cells. Tissue Eng Part A. 2008;14:529-537
128. Wirrig EE, Gomez MV, Hinton RB, Yutzey KE. COX2 inhibition reduces aortic valve calcification in vivo. Arterioscler Thromb Vasc Biol. 2015;35:938-947
129. Baek D, Villen J, Shin C, Camargo FD, Gygi SP, Bartel DP. The impact of microRNAs on protein output. Nature. 2008;455:64-71
130. Nagy E, Back M. Epigenetic regulation of 5-lipoxygenase in the phenotypic plasticity of valvular interstitial cells associated with aortic valve stenosis. FEBS Lett. 2012;586:1325-1329
131. Euler-Taimor G, Heger J. The complex pattern of SMAD signaling in the cardiovascular system. Cardiovasc Res. 2006;69:15-25
132. Li X, Lim J, Lu J, Pedego TM, Demer L, Tintut Y. Protective role of Smad6 in inflammation-induced valvular cell calcification. J Cell Biochem. 2015;116:2354-2364
133. Bialek P, Kern B, Yang X, Schrock M, Sosic D, Hong N, Wu H, Yu K, Ornitz DM, Olson EN, Justice MJ, Karsenty G. A twist code determines the onset of osteoblast differentiation. Dev Cell. 2004;6:423-435