[en] Calcific Aortic Valve Disease (CAVD) is the most common heart valve disease and its incidence is expected to rise with aging population. No medical treatment so far has shown slowing progression of CAVD progression. Surgery remains to this day the only way to treat it. Effective drug therapy can only be achieved through a better insight into the pathogenic mechanisms underlying CAVD. The cellular and molecular events leading to leaflets calcification are complex. Upon endothelium cell damage, oxidized LDLs trigger a proinflammatory response disrupting healthy cross-talk between valve endothelial and interstitial cells. Therefore, valve interstitial cells transform into osteoblasts and mineralize the leaflets. Studies have investigated signaling pathways driving and connecting lipid metabolism, inflammation and osteogenesis. This review draws a summary of the recent advances and discusses their exploitation as promising therapeutic targets to treat CAVD and reduce valve replacement.
Disciplines :
Cardiovascular & respiratory systems
Author, co-author :
Hulin, Alexia ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > GIGA-R : GIGA - Cardiovascular Sciences
Lindman BR, Clavel MA, Mathieu P, Iung B, Lancellotti P, Otto CM, et al. Calcific aortic stenosis. Nat Rev Dis Primers (2016) 2:16006. 10.1038/nrdp.2016.6
Yutzey KE, Demer LL, Body SC, Huggins GS, Towler DA, Giachelli CM, et al. Calcific aortic valve disease: a consensus summary from the alliance of Investigators on calcific aortic valve disease. Arterioscler Thromb Vasc Biol (2014) 34(11):2387–93. 10.1161/ATVBAHA.114.302523
Nkomo VT, Gardin JM, Skelton TN, Gottdiener JS, Scott CG, Enriquez-Sarano M. Burden of valvular heart diseases: a population-based study. Lancet (2006) 368(9540):1005–11. 10.1016/S0140-6736(06)69208-8
Benjamin EJ, Blaha MJ, Chiuve SE, Cushman M, Das SR, Deo R, et al. Heart disease and stroke statistics-2017 update: a report from the American heart association. Circulation (2017) 135(10):e146–603. 10.1161/CIR.0000000000000485
Hutcheson JD, Aikawa E, Merryman WD. Potential drug targets for calcific aortic valve disease. Nat Rev Cardiol (2014) 11(4):218–31. 10.1038/nrcardio.2014.1
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(16):1783–91. 10.1161/CIRCULATIONAHA.110.006767
Mosch J, Gleissner CA, Body S, Aikawa E. Histopathological assessment of calcification and inflammation of calcific aortic valves from patients with and without diabetes mellitus. Histol Histopathol (2017) 32(3):293–306. 10.14670/HH-11-797
Stewart BF, Siscovick D, Lind BK, Gardin JM, Gottdiener JS, Smith VE, et al. Clinical factors associated with calcific aortic valve disease. Cardiovascular health study. J Am Coll Cardiol (1997) 29(3):630–4.
Testuz A, Nguyen V, Mathieu T, Kerneis C, Arangalage D, Kubota N, et al. Influence of metabolic syndrome and diabetes on progression of calcific aortic valve stenosis. Int J Cardiol (2017) 244:248–53. 10.1016/j.ijcard.2017.06.104
Sider KL, Blaser MC, Simmons CA. Animal models of calcific aortic valve disease. Int J Inflam (2011) 2011:1–18. 10.4061/2011/364310
Ghaisas NK, Foley JB, O'Briain DS, Crean P, Kelleher D, Walsh M. Adhesion molecules in nonrheumatic aortic valve disease: endothelial expression, serum levels and effects of valve replacement. J Am Coll Cardiol (2000) 36(7):2257–62. 10.1016/S0735-1097(00)00998-0
Poggianti E, Venneri L, Chubuchny V, Jambrik Z, Baroncini LA, Picano E. Aortic valve sclerosis is associated with systemic endothelial dysfunction. J Am Coll Cardiol (2003) 41(1):136–41. 10.1016/S0735-1097(02)02622-0
Sucosky P, Balachandran K, Elhammali A, Jo H, Yoganathan AP. Altered shear stress stimulates upregulation of endothelial VCAM-1 and ICAM-1 in a BMP-4- and TGF-beta1-dependent pathway. Arterioscler Thromb Vasc Biol (2009) 29(2):254–60. 10.1161/ATVBAHA.108.176347
Gould ST, Srigunapalan S, Simmons CA, Anseth KS. Hemodynamic and cellular response feedback in calcific aortic valve disease. Circ Res (2013) 113(2):186–97. 10.1161/CIRCRESAHA.112.300154
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(7):792–9. 10.1161/01.RES.0000161998.92009.64
Yap CH, Saikrishnan N, Yoganathan AP. Experimental measurement of dynamic fluid shear stress on the ventricular surface of the aortic valve leaflet. Biomech Model Mechanobiol (2012) 11(1-2):231–44. 10.1007/s10237-011-0306-2
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(7):920–5. 10.1161/01.CIR.0000155623.48408.C5
Meierhofer C, Schneider EP, Lyko C, Hutter A, Martinoff S, Markl M, et al. Wall shear stress and flow patterns in the ascending aorta in patients with bicuspid aortic valves differ significantly from tricuspid aortic valves: a prospective study. Eur Heart J Cardiovasc Imaging (2013) 14(8):797–804. 10.1093/ehjci/jes273
Saikrishnan N, Mirabella L, Yoganathan AP. Bicuspid aortic valves are associated with increased wall and turbulence shear stress levels compared to trileaflet aortic valves. Biomech Model Mechanobiol (2015) 14(3):577–88. 10.1007/s10237-014-0623-3
Otto CM, Kuusisto J, Reichenbach DD, Gown AM, O'Brien KD. Characterization of the early lesion of 'degenerative' valvular aortic stenosis. Histological and immunohistochemical studies. Circulation (1994) 90(2):844–53. 10.1161/01.CIR.90.2.844
Porras AM, Shanmuganayagam D, Meudt JJ, Krueger CG, Hacker TA, Rahko PS, et al. Development of aortic valve disease in familial hypercholesterolemic swine: implications for elucidating disease etiology. J Am Heart Assoc (2015) 4(10):e002254. 10.1161/JAHA.115.002254
Rajamannan NM. The role of Lrp5/6 in cardiac valve disease: experimental hypercholesterolemia in the ApoE-/- /Lrp5-/- mice. J Cell Biochem (2011a) 112(10):2987–91. 10.1002/jcb.23221
Varghese MJ. Familial hypercholesterolemia: a review. Ann Pediatr Cardiol (2014) 7(2):107. 10.4103/0974-2069.132478
Sider KL, Zhu C, Kwong AV, Mirzaei Z, de Langé CF, Simmons CA. Evaluation of a porcine model of early aortic valve sclerosis. Cardiovasc Pathol (2014) 23(5):289–97. 10.1016/j.carpath.2014.05.004
Chan KL, Teo K, Dumesnil JG, Ni A, Tam J, ASTRONOMER Investigators. Effect of Lipid lowering with rosuvastatin on progression of aortic stenosis: results of the aortic stenosis progression observation: measuring effects of rosuvastatin (ASTRONOMER) trial. Circulation (2010) 121(2):306–14. 10.1161/CIRCULATIONAHA.109.900027
Cowell SJ, Newby DE, Prescott RJ, Bloomfield P, Reid J, Northridge DB, et al. A randomized trial of intensive lipid-lowering therapy in calcific aortic stenosis. N Engl J Med (2005) 352(23):2389–97. 10.1056/NEJMoa043876
Rossebø AB, Pedersen TR, Boman K, Brudi P, Chambers JB, Egstrup K, et al. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med (2008) 359(13):1343–56. 10.1056/NEJMoa0804602
Kostner GM, Gavish D, Leopold B, Bolzano K, Weintraub MS, Breslow JL. HMG CoA reductase inhibitors lower LDL cholesterol without reducing Lp(a) levels. Circulation (1989) 80(5):1313–9. 10.1161/01.CIR.80.5.1313
Peeters FECM, Meex SJR, Dweck MR, Aikawa E, Crijns HJGM, Schurgers LJ, et al. Calcific aortic valve stenosis: hard disease in the heart. Eur Heart J (2017) 131. 10.1093/eurheartj/ehx653
Rogers MA, Aikawa E. A Not-So-Little Role for Lipoprotein(a) in the Development of Calcific Aortic Valve Disease. Circulation (2015) 132(8):621–3. 10.1161/CIRCULATIONAHA.115.018139
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(4):523–32. 10.1161/01.ATV.16.4.523
Arsenault BJ, Boekholdt SM, Dubé MP, Rhéaume E, Wareham NJ, Khaw KT, et al. Lipoprotein(a) levels, genotype, and incident aortic valve stenosis: a prospective Mendelian randomization study and replication in a case-control cohort. Circ Cardiovasc Genet (2014) 7(3):304–10. 10.1161/CIRCGENETICS.113.000400
Kamstrup PR, Tybjærg-Hansen A, Nordestgaard BG. Elevated lipoprotein(a) and risk of aortic valve stenosis in the general population. J Am Coll Cardiol (2014) 63(5):470–7. 10.1016/j.jacc.2013.09.038
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(6):503–12. 10.1056/NEJMoa1109034
Tsimikas S, Fazio S, Ferdinand KC, Ginsberg HN, Koschinsky ML, Marcovina SM, et al. NHLBI working group recommendations to reduce lipoprotein(a)-mediated risk of cardiovascular disease and aortic stenosis. J Am Coll Cardiol (2018) 71(2):177–92. 10.1016/j.jacc.2017.11.014
Lehti S, Käkelä R, Hörkkö S, Kummu O, Helske-Suihko S, Kupari M, et al. Modified lipoprotein-derived lipid particles accumulate in human stenotic aortic valves. PLoS ONE (2013) 8(6):e65810. 10.1371/journal.pone.0065810
Mahmut A, Boulanger MC, El Husseini D, Fournier D, Bouchareb R, Després 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(5):460–9. 10.1016/j.jacc.2013.05.105
Bouchareb R, Mahmut A, Nsaibia MJ, Boulanger MC, Dahou A, Lépine JL, et al. Autotaxin derived from lipoprotein(a) and valve interstitial cells promotes inflammation and mineralization of the aortic valve. Circulation (2015) 132(8):677–90. 10.1161/CIRCULATIONAHA.115.016757
Nsaibia MJ, Boulanger MC, Bouchareb R, Mkannez G, Le Quang K, Hadji F, et al. OxLDL-derived lysophosphatidic acid promotes the progression of aortic valve stenosis through a LPAR1-RhoA-NF-κB pathway. Cardiovasc Res (2017) 113(11):1351–63. 10.1093/cvr/cvx089
Farrar EJ, Pramil V, Richards JM, Mosher CZ, Butcher JT. Valve interstitial cell tensional homeostasis directs calcification and extracellular matrix remodeling processes via RhoA signaling. Biomaterials (2016) 105:25–37. 10.1016/j.biomaterials.2016.07.034
Osman N, Grande-Allen KJ, Ballinger ML, Getachew R, Marasco S, O'Brien KD, et al. Smad2-dependent glycosaminoglycan elongation in aortic valve interstitial cells enhances binding of LDL to proteoglycans. Cardiovasc Pathol (2013) 22(2):146–55. 10.1016/j.carpath.2012.07.002
Porras AM, Westlund JA, Evans AD, Masters KS. Creation of disease-inspired biomaterial environments to mimic pathological events in early calcific aortic valve disease. Proc Natl Acad Sci USA (2018) 115(3):E363–71. 10.1073/pnas.1704637115
Viney NJ, van Capelleveen JC, Geary RS, Xia S, Tami JA, Yu RZ, et al. Antisense oligonucleotides targeting apolipoprotein(a) in people with raised lipoprotein(a): two randomised, double-blind, placebo-controlled, dose-ranging trials. Lancet (2016) 388(10057):2239–53. 10.1016/S0140-6736(16)31009-1
Karatasakis A, Danek BA, Karacsonyi J, Rangan BV, Roesle MK, Knickelbine T, et al. Effect of PCSK9 inhibitors on clinical outcomes in patients with hypercholesterolemia: a meta-analysis of 35 randomized controlled trials. J Am Heart Assoc (2017) 6(12):e006910. 10.1161/JAHA.117.006910
Fitzgerald K, White S, Borodovsky A, Bettencourt BR, Strahs A, Clausen V, et al. A highly durable RNAi therapeutic inhibitor of PCSK9. N Engl J Med (2017) 376(1):41–51. 10.1056/NEJMoa1609243
Ray KK, Landmesser U, Leiter LA, Kallend D, Dufour R, Karakas M, et al. Inclisiran in patients at high cardiovascular risk with elevated LDL cholesterol. N Engl J Med (2017) 376(15):1430–40. 10.1056/NEJMoa1615758
Bossé Y, Miqdad A, Fournier D, Pépin A, Pibarot P, Mathieu P. Refining molecular pathways leading to calcific aortic valve stenosis by studying gene expression profile of normal and calcified stenotic human aortic valves. Circ Cardiovasc Genet (2009) 2(5):489 10.1161/CIRCGENETICS.108.820795
Coté N, Mahmut A, Bosse Y, Couture C, Pagé S, Trahan S, et al. Inflammation is associated with the remodeling of calcific aortic valve disease. Inflammation (2013) 36(3):573–81. 10.1007/s10753-012-9579-6
Mohler ER, Gannon F, Reynolds C, Zimmerman R, Keane MG, Kaplan FS. Bone formation and inflammation in cardiac valves. Circulation (2001) 103(11):1522–8. 10.1161/01.CIR.103.11.1522
Dweck MR, Jones C, Joshi NV, Fletcher AM, Richardson H, White A, et al. Assessment of valvular calcification and inflammation by positron emission tomography in patients with aortic stenosis. Circulation (2012) 125(1):76–86. 10.1161/CIRCULATIONAHA.111.051052
Lee SH, Choi JH. Involvement of immune cell network in aortic valve stenosis: communication between valvular interstitial cells and immune cells. Immune Netw (2016) 16(1):26–32. 10.4110/in.2016.16.1.26
Mathieu P, Bouchareb R, Boulanger MC. Innate and adaptive immunity in calcific aortic valve disease. J Immunol Res (2015) 2015:1–11. 10.1155/2015/851945
Côté C, Pibarot P, Després JP, Mohty D, Cartier A, Arsenault BJ, et al. Association between circulating oxidised low-density lipoprotein and fibrocalcific remodelling of the aortic valve in aortic stenosis. Heart (2008) 94(9):1175–80. 10.1136/hrt.2007.125740
Olsson M, Dalsgaard CJ, Haegerstrand A, Rosenqvist M, Rydén L, Nilsson J. Accumulation of T lymphocytes and expression of interleukin-2 receptors in nonrheumatic stenotic aortic valves. J Am Coll Cardiol (1994) 23(5):1162–70. 10.1016/0735-1097(94)90606-8
Kaden JJ, Dempfle CE, Grobholz R, Tran HT, Kiliç R, Sarikoç A, et al. Interleukin-1 beta promotes matrix metalloproteinase expression and cell proliferation in calcific aortic valve stenosis. Atherosclerosis (2003) 170(2):205–11. 10.1016/S0021-9150(03)00284-3
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(4):708–15. 10.1161/ATVBAHA.109.201749
Kaden JJ, Kiliç R, Sarikoç A, Hagl S, Lang S, Hoffmann U, et al. Tumor necrosis factor alpha promotes an osteoblast-like phenotype in human aortic valve myofibroblasts: a potential regulatory mechanism of valvular calcification. Int J Mol Med (2005) 16(5):869–72. 10.3892/ijmm.16.5.869
Li G, Qiao W, Zhang W, Li F, Shi J, Dong N. The shift of macrophages toward M1 phenotype promotes aortic valvular calcification. J Thorac Cardiovasc Surg (2017) 153(6):1318–27. 10.1016/j.jtcvs.2017.01.052
Edep ME, Shirani J, Wolf P, Brown DL. Matrix metalloproteinase expression in nonrheumatic aortic stenosis. Cardiovasc. Pathol. (2000) 9(5):281–6. 10.1016/S1054-8807(00)00043-0
Li XF, Wang Y, Zheng DD, Xu HX, Wang T, Pan M, et al. M1 macrophages promote aortic valve calcification mediated by microRNA-214/TWIST1 pathway in valvular interstitial cells. Am J Transl Res (2016) 8(12):5773–83.
Kaden JJ, Bickelhaupt S, Grobholz R, Haase KK, Sarikoç A, Kiliç R, et al. Receptor activator of nuclear factor kappaB ligand and osteoprotegerin regulate aortic valve calcification. J Mol Cell Cardiol (2004) 36(1):57–66. 10.1016/j.yjmcc.2003.09.015
Nagy E, Lei Y, Martínez-Martínez E, Body SC, Schlotter F, Creager M, et al. Interferon-γ released by activated CD8+T lymphocytes impairs the calcium resorption potential of osteoclasts in calcified human aortic valves. Am J Pathol (2017) 187(6):1413–25. 10.1016/j.ajpath.2017.02.012
Winchester R, Wiesendanger M, O'Brien W, Zhang HZ, Maurer MS, Gillam LD, et al. Circulating activated and effector memory T cells are associated with calcification and clonal expansions in bicuspid and tricuspid valves of calcific aortic stenosis. J Immunol (2011) 187(2):1006–14. 10.4049/jimmunol.1003521
Chinetti-Gbaguidi G, Daoudi M, Rosa M, Vinod M, Louvet L, Copin C, et al. Human alternative macrophages populate calcified areas of atherosclerotic lesions and display impaired RANKL-induced osteoclastic bone resorption activity. Circ Res (2017) 121(1):19–30. 10.1161/CIRCRESAHA.116.310262
Shimoni S, Bar I, Meledin V, Gandelman G, George J. Circulating regulatory T cells in patients with aortic valve stenosis: association with disease progression and aortic valve intervention. Int J Cardiol (2016) 218:181–7. 10.1016/j.ijcard.2016.05.039
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(3):497–505. 10.1084/jem.20082129
Mahler GJ, Farrar EJ, Butcher JT. Inflammatory cytokines promote mesenchymal transformation in embryonic and adult valve endothelial cells. Arterioscler Thromb Vasc Biol (2013) 33(1):121–30. 10.1161/ATVBAHA.112.300504
Richards J, El-Hamamsy I, Chen S, Sarang Z, Sarathchandra P, Yacoub MH, et al. Side-specific endothelial-dependent regulation of aortic valve calcification. Am J Pathol (2013) 182(5):1922–31. 10.1016/j.ajpath.2013.01.037
Rajamannan NM, Subramaniam M, Stock SR, Stone NJ, Springett M, Ignatiev KI, et al. Atorvastatin inhibits calcification and enhances nitric oxide synthase production in the hypercholesterolaemic aortic valve. Heart (2005) 91(6):806–10. 10.1136/hrt.2003.029785
Davis ME, Grumbach IM, Fukai T, Cutchins A, Harrison DG. Shear stress regulates endothelial nitric-oxide synthase promoter activity through nuclear factor kappaB binding. J Biol Chem (2004) 279(1):163–8. 10.1074/jbc.M307528200
Lubrano V, Vassalle C, Blandizzi C, del Tacca M, Palombo C, L'Abbate A, et al. The effect of lipoproteins on endothelial nitric oxide synthase is modulated by lipoperoxides. Eur J Clin Invest (2003) 33(2):117–25. 10.1046/j.1365-2362.2003.01083.x
Miller JD, Chu Y, Brooks RM, Richenbacher WE, Peña-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(10):843–50. 10.1016/j.jacc.2008.05.043
Choi B, Lee S, Kim SM, Lee EJ, Lee SR, Kim DH, et al. Dipeptidyl peptidase-4 induces aortic valve calcifcation by inhibiting insulin-like growth factor-1 signaling in valvular interstitial cells. Circulation (2017) 135(20):1935–50. 10.1161/CIRCULATIONAHA.116.024270
Huk DJ, Austin BF, Horne TE, Hinton RB, Ray WC, Heistad DD, et al. Valve endothelial cell-derived Tgfβ1 signaling promotes nuclear localization of Sox9 in interstitial cells associated with attenuated calcification. Arterioscler Thromb Vasc Biol (2016) 36(2):328–38. 10.1161/ATVBAHA.115.306091
Peacock JD, Levay AK, Gillaspie DB, Tao G, Lincoln J. Reduced sox9 function promotes heart valve calcification phenotypes in vivo. Circ Res (2010) 106(4):712–9. 10.1161/CIRCRESAHA.109.213702
Song R, Zeng Q, Ao L, Yu JA, Cleveland JC, Zhao KS, et al. Biglycan induces the expression of osteogenic factors in human aortic valve interstitial cells via Toll-like receptor-2. Arterioscler Thromb Vasc Biol (2012) 32(11):2711–20. 10.1161/ATVBAHA.112.300116
Zeng Q, Song R, Fullerton DA, Ao L, Zhai Y, Li S, et al. Interleukin-37 suppresses the osteogenic responses of human aortic valve interstitial cells in vitro and alleviates valve lesions in mice. Proc Natl Acad Sci USA (2017) 114(7):1631–6. 10.1073/pnas.1619667114
Zhan Q, Song R, Zeng Q, Yao Q, Ao L, Xu D, et al. Activation of TLR3 induces osteogenic responses in human aortic valve interstitial cells through the NF-κB and ERK1/2 pathways. Int J Biol Sci (2015) 11(4):482–93. 10.7150/ijbs.10905
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-κB interaction. PLoS ONE (2014) 9(5):e95400. 10.1371/journal.pone.0095400
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(8):1707–12. 10.1016/j.jacc.2006.02.040
Wirrig EE, Hinton RB, Yutzey KE. Differential expression of cartilage and bone-related proteins in pediatric and adult diseased aortic valves. J Mol Cell Cardiol (2011) 50(3):561–9. 10.1016/j.yjmcc.2010.12.005
Cheek JD, Wirrig EE, Alfieri CM, James JF, Yutzey KE. Differential activation of valvulogenic, chondrogenic, and osteogenic pathways in mouse models of myxomatous and calcific aortic valve disease. J Mol Cell Cardiol (2012) 52(3):689–700. 10.1016/j.yjmcc.2011.12.013
Ankeny RF, Thourani VH, Weiss D, Vega JD, Taylor WR, Nerem RM, et al. Preferential activation of SMAD1/5/8 on the fibrosa endothelium in calcified human aortic valves-association with low BMP antagonists and SMAD6. PLoS ONE (2011) 6(6):e20969. 10.1371/journal.pone.0020969
Gomez-Stallons MV, Wirrig-Schwendeman EE, Hassel KR, Conway SJ, Yutzey KE, Bone Morphogenetic Protein Signaling Is Required for Aortic Valve Calcification. Arterioscler. Thromb. Vasc. Biol. (2016) 36(7):1398–405.
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(10):2354–64. 10.1002/jcb.25186
Garg V, Muth AN, Ransom JF, Schluterman MK, Barnes R, King IN, et al. Mutations in NOTCH1 cause aortic valve disease. Nature (2005) 437(7056):270–4. 10.1038/nature03940
Acharya A, Hans CP, Koenig SN, Nichols HA, Galindo CL, Garner HR, et al. Inhibitory role of Notch1 in calcific aortic valve disease. PLoS ONE (2011) 6(11):e27743. 10.1371/journal.pone.0027743
Nigam V, Srivastava D. Notch1 represses osteogenic pathways in aortic valve cells. J Mol Cell Cardiol (2009) 47(6):828–34. 10.1016/j.yjmcc.2009.08.008
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. 10.1016/j.yjmcc.2013.04.001
Hadji F, Boulanger MC, Guay SP, Gaudreault N, Amellah S, Mkannez G, et al. Altered DNA methylation of long noncoding RNA H19 in calcific aortic valve disease promotes mineralization by silencing NOTCH1. Circulation (2016) 134(23):1848–62. 10.1161/CIRCULATIONAHA.116.023116
Arikawa T, Omura K, Morita I. Regulation of bone morphogenetic protein-2 expression by endogenous prostaglandin E2 in human mesenchymal stem cells. J Cell Physiol (2004) 200(3):400–6. 10.1002/jcp.20031
Zhang X, Schwarz EM, Young DA, Puzas JE, Rosier RN, O'Keefe RJ. Cyclooxygenase-2 regulates mesenchymal cell differentiation into the osteoblast lineage and is critically involved in bone repair. J Clin Invest (2002) 109(11):1405–15. 10.1172/JCI0215681
Singh G, Fort JG, Goldstein JL, Levy RA, Hanrahan PS, Bello AE, et al. Celecoxib versus naproxen and diclofenac in osteoarthritis patients: SUCCESS-I Study. Am J Med (2006) 119(3):255–66. 10.1016/j.amjmed.2005.09.054
Solomon SD, McMurray JJ, Pfeffer MA, Wittes J, Fowler R, Finn P, et al. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med (2005) 352(11):1071–80. 10.1056/NEJMoa050405
Pepine CJ, Gurbel PA. Cardiovascular safety of NSAIDs: Additional insights after PRECISION and point of view. Clin Cardiol (2017) 40(12):1352–1356. 10.1002/clc.22814
Nissen SE, Yeomans ND, Solomon DH, Lüscher TF, Libby P, Husni ME, et al. Cardiovascular safety of celecoxib, naproxen, or ibuprofen for arthritis. N Engl J Med (2016) 375(26):2519–29. 10.1056/NEJMoa1611593
Albanese I, Yu B, Al-Kindi H, Barratt B, Ott L, Al-Refai M, et al. Role of noncanonical wnt signaling pathway in human aortic valve calcification. Arterioscler Thromb Vasc Biol (2017) 37(3):543–52. 10.1161/ATVBAHA.116.308394
Siddique A, Yu B, Khan K, Buyting R, Al-Kindi H, Alaws H, et al. Expression of the Frizzled receptors and their co-receptors in calcified human aortic valves. Can J Physiol Pharmacol (2018) 96(2):208–14. 10.1139/cjpp-2017-0577
Alfieri CM, Cheek J, Chakraborty S, Yutzey KE. Wnt signaling in heart valve development and osteogenic gene induction. Dev Biol (2010) 338(2):127–35. 10.1016/j.ydbio.2009.11.030
Fang M, Alfieri CM, Hulin A, Conway SJ, Yutzey KE. Loss of β-catenin promotes chondrogenic differentiation of aortic valve interstitial cells. Arterioscler Thromb Vasc Biol (2014) 34(12):2601–8. 10.1161/ATVBAHA.114.304579
Rajamannan NM. The role of Lrp5/6 in cardiac valve disease: LDL-density-pressure theory. J Cell Biochem (2011b) 112(9):2222–9. 10.1002/jcb.23182
Hulin A, Moore V, James JM, Yutzey KE. Loss of Axin2 results in impaired heart valve maturation and subsequent myxomatous valve disease. Cardiovasc Res (2017) 113(1):40–51. 10.1093/cvr/cvw229
Kahn M. Can we safely target the WNT pathway? Nat Rev Drug Discov (2014) 13(7):513–32. 10.1038/nrd4233