Summary.
Objectives. Aortic stenosis is the leading cause of heart valve disease in elderly. Little is known about molecular mechanisms leading to altered left ventricular geometry generally and, particularly, to remodeling of degenerating aortic valve. Alterations in native degenerating aortic valves and valvular tissue after replacement might result from a stage specific tissue remodeling protein core induced by stress responsible factors. Here we were looking for a possible stage specificity of tissue remodeling and stress responsive checkpoint gene activation in native degenerating human aortic valves and bioprosthetic valvular tissue after replacement.
Materials and methods. Specimens of native degenerating aortic valves as well as bioprosthetic valves after replacement were tested for their morphological properties. Native degenerating valves were selected for two groups: non-calcified (7 samples) and calcified (5 samples) one; the third group (5 samples) was consisting of bioprosthetic valve samples after replacement. Individual mRNA-pools were isolated from each tissue sample, and semi-quantitative RT-PCR was performed. Target transcripts of p21waf1/cip1, MT1-MMP, MMP-2, MMP-9 and TIMP-1 were measured. The specificity was controlled by restriction analysis of PCR products.
Results and conclusions. According to the abundant expression of p21waf1/cip1, a highly activated stress response was found in non-calcified native degenerating aortic valves, whereas no stress response was monitored in valvular tissue after replacement. Whereas MT1-MMP expression was almost equally induced in all three groups investigated, MMP-9 was higher expressed in non-calcified versus calcified native valves, and was not expressed after replacement. An induced expression of MMP-2 was detected in non-calcified native degenerating aortic valves only. An abundant expression of tissue inhibitor of metalloproteinases TIMP-1 was observed in all three groups tested. Apparently, the ECM degradation potential is specifically enhanced in non-calcified native degenerating aortic valves e.g. at the early degeneration stages. In contrast, the replaced valves were found to be actively resorbing tissue with no detectable stress response, where both MT1-MMP and TIMP-1 might play the key role in geometry remodeling.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
S Blankenberg HJ Rupprecht O Poirier C Bickel M Smieja G Hafner J Meyer F Cambien L Tiret InstitutionalAuthorNameAtheroGene Investigators (2003) ArticleTitlePlasma concentrations and genetic variation of matrix metalloproteinase 9 and prognosis of patients with cardiovascular disease Circulation 107 1579–1585 Occurrence Handle12668489 Occurrence Handle1:CAS:528:DC%2BD3sXit12msLo%3D Occurrence Handle10.1161/01.CIR.0000058700.41738.12
BD Chang K Watanabe EV Broude J Fang JC Poole TV Kalinichenko IB Roninson (2000) ArticleTitleEffects of p21Wafl/Cipl/Sdil on cellular gene expression: implications for carcinogenesis, senescence, and age-related diseases Proc Natl Acad Sci USA 97 4291–4296 Occurrence Handle10760295 Occurrence Handle1:CAS:528:DC%2BD3cXislSnsrs%3D Occurrence Handle10.1073/pnas.97.8.4291
Y Chen A Belboul E Berglin D Roberts (2000) ArticleTitleA mathematical analysis of hemorheological changes during heart valve replacement J Cardiovasc Surg (Torino) 41 37–43 Occurrence Handle1:STN:280:DC%2BD3c3psVajug%3D%3D
BP Chen YS Li Y Zhao KD Chen S Li J Lao S Yuan JY Shyy S Chien (2001) ArticleTitleDNA microarray analysis of gene expression in endothelial cells in response to 24-h shear stress Physiol Genomics 7 55–63 Occurrence Handle11595792 Occurrence Handle1:CAS:528:DC%2BD3MXjslKhtbs%3D Occurrence Handle10.1006/geno.2001.6511
AJ Gearing P Beckett M Christodoulou M Churchill J Clements AH Davidson AH Drummond WA Galloway R Gilbert JL Gordon TM Leber M Mangan K Miller P Nayee K Owen S Patel W Thomas G Wells LM Wood K Woolley (1994) ArticleTitleProcessing of tumour necrosis factor-α precursor by metalloproteinases Nature 370 555–557 Occurrence Handle8052310 Occurrence Handle1:CAS:528:DyaK2cXlsFGnsLg%3D Occurrence Handle10.1038/370555a0
O Golubnitschaja H Moenkemann K Kim MS Mozaffari (2003) ArticleTitleDNA damage and expression of checkpoint genes p21(WAF1/CIP1) and 14-3-3 sigma in taurine-deficient cardiomyocytes Biochem Pharmacol 66 511–517 Occurrence Handle12907251 Occurrence Handle1:CAS:528:DC%2BD3sXlvFygt7g%3D Occurrence Handle10.1016/S0006-2952(03)00285-5
O Golubnitschaja H Moenkemann DB Trog HJ Blom AS De Vriese (2006) ArticleTitleActivation of genes inducing cell-cycle arrest and of increased DNA repair in the hearts of rats with early streptozotocin-induced diabetes mellitus Med Sci Monit 12 BR68–BR74 Occurrence Handle16449944 Occurrence Handle1:CAS:528:DC%2BD28Xit1ylt7c%3D
T Hattori A Sakai K Ihashi S Kasahara M Oosawa (1994) ArticleTitleMitral and aortic valve replacement associated with aortitis syndrome: a case report Kyobu Geka 47 1016–1019 Occurrence Handle7990279 Occurrence Handle1:STN:280:ByqD1c3hs1M%3D
K Horiguchi S Ohtake G Matsumiya Y Sawa M Nishimura H Satou N Kawai H Matsuda (2001) ArticleTitleAortic valve replacement combined with endoventricular circulatory patch plasty (Dor operation) in a patient with aortic valve stenosis and severe ischemic cardiomyopathy Ann Thorac Cardiovasc Surg 7 170–174 Occurrence Handle11481025 Occurrence Handle1:STN:280:DC%2BD3Mvjt1GisA%3D%3D
K Imai E Obuchi T Aoki H Nomura Y Fujii H Sato M Seiki Y Okada (1996) ArticleTitleMembrane-type matrix metalloproteinase 1 is a gelatinolytic enzyme and is secreted in a complex with tissue inhibitor of metalloproteinases Cancer Res 56 2707–2710 Occurrence Handle8665498 Occurrence Handle1:CAS:528:DyaK28XjsFGkurc%3D
JJ Kaden DC Vocke CS Fischer R Grobholz M Brueckmann CF Vahl S Hagl KK Haase CE Dempfle M Borggrefe (2004) ArticleTitleExpression and activity of matrix metalloproteinase-2 in calcific aortic stenosis Z Kardiol 93 124–130 Occurrence Handle14963678 Occurrence Handle1:CAS:528:DC%2BD2cXjtFKmsb0%3D Occurrence Handle10.1007/s00392-004-1021-0
KM Kim (1995) ArticleTitleApoptosis and calcification Scanning Microsc 9 1137–1178 Occurrence Handle8819895 Occurrence Handle1:CAS:528:DyaK28XhtFyrsr4%3D
KJ Leco R Khokha N Pavloff SP Hawkes DR Edwards (1994) ArticleTitleTissue inhibitor of metalloproteinases-3 (TIMP-3) is an extracellular matrix-associated protein with a distinctive pattern of expression in mouse cells and tissues J Biol Chem 269 9352–9360 Occurrence Handle8132674 Occurrence Handle1:CAS:528:DyaK2cXktVels7Y%3D
J Lohi K Lehti H Valtanen WC Parks J Keski-Oja (2000) ArticleTitleStructural analysis and promoter characterization of the human membrane-type matrix metalloproteinase-1 (MT1-MMP) gene Gene 242 75–86 Occurrence Handle10721699 Occurrence Handle1:CAS:528:DC%2BD3cXhsFCjt78%3D Occurrence Handle10.1016/S0378-1119(99)00549-1
C Mantel SE Braun S Reid O Henegariu L Liu G Hangoc HE Broxmeyer (1999) ArticleTitlep21(cip-1/waf-1) deficiency causes deformed nuclear architecture, centriole overduplication, polypioidy, and relaxed microtubule damage checkpoints in human hematopoietic cells Blood 93 1390–1398 Occurrence Handle9949183 Occurrence Handle1:CAS:528:DyaK1MXht1Cju70%3D
GM McGeehan JD Becherer RC Bast SuffixJr CM Boyer B Champion KM Connolly JG Conway P Furdon S Karp S Kidao AB McElroy J Nichols KM Pryzwansky F Schoenen L Sekut A Truesdale M Verghese J Warner JP Ways (1994) ArticleTitleRegulation of tumour necrosis factor-α processing by a metalloproteinase inhibitor Nature 370 558–561 Occurrence Handle8052311 Occurrence Handle1:CAS:528:DyaK2cXmtVaqt7g%3D Occurrence Handle10.1038/370558a0
T Murakami D Kikugawa K Endou Y Fukuhiro A Ishida I Morita H Masaki H Inada T Fujiwara (2000) ArticleTitleChanges in patterns of left ventricular hypertrophy after aortic valve replacement for aortic stenosis and regurgitation with St. Jude Medical cardiac valves Artif Organs 24 953–958 Occurrence Handle11121975 Occurrence Handle1:STN:280:DC%2BD3M%2FpsVakug%3D%3D Occurrence Handle10.1046/j.1525-1594.2000.06641.x
GM Novaro GL Pearce DL Sprecher BP Griffin (2001) ArticleTitleComparison of cardiovascular risk and lipid profiles in patients undergoing aortic valve surgery versus those undergoing coronary artery bypass grafting J Heart Valve Dis 10 19–24 Occurrence Handle11206763 Occurrence Handle1:STN:280:DC%2BD3M3isVegtg%3D%3D
S Pietri JR Seguin PD d’Arbigny M Culcasi (1994) ArticleTitleAscorbyl free radical: a noninvasive marker of oxidative stress in human open-heart surgery Free Radic Biol Med 16 523–528 Occurrence Handle8005538 Occurrence Handle1:STN:280:ByuB2svhsVc%3D Occurrence Handle10.1016/0891-5849(94)90131-7
D Skowasch S Schrempf N Wernert M Steinmetz A Jabs I Tuleta U Welsch CJ Preusse JA Likungu A Welz B Luderitz G Bauriedel (2005) ArticleTitleCells of primarily extra-valvular origin in degenerative aortic valves and bioprostheses Eur Heart J 26 2576–2580 Occurrence Handle16115807 Occurrence Handle10.1093/eurheartj/ehi458
SS Srivatsa PJ Harrity PB Maercklein L Kleppe J Veinot WD Edwards CM Johnson LA Fitzpatrick (1997) ArticleTitleIncreased cellular expression of matrix proteins that regulate mineralization is associated with calcification of native human and porcine xenograft bioprosthetic heart valves J Clin Invest 99 996–1009 Occurrence Handle9062358 Occurrence Handle1:STN:280:ByiB3Mngs1w%3D Occurrence Handle10.1172/JCI119265
Y Sugiyama H Hirai A Ohta T Inoue T Lee M Harada M Suzuki S Tamura K Shiroma K Ebine K Takahashi T Yamaguchi (1997) ArticleTitleSevere aortic regurgitation with marked thickening of the aortic annulus: a case report J Cardiol 29 81–86 Occurrence Handle9211107
PM Taylor SP Allen MH Yacoub (2000) ArticleTitlePhenotypic and functional characterization of interstitial cells from human heart valves, pericardium and skin J Heart Valve Dis 9 150–158 Occurrence Handle10678389 Occurrence Handle1:STN:280:DC%2BD3c7ktFymtQ%3D%3D
M Vrandecic FA Fantini BG Filho OC de Oliveira IM da Costa Junior E Vrandecic (2000) ArticleTitleRetrospective clinical analysis of stented vs. stentless porcine aortic bioprostheses Eur J Cardiothorac Surg 18 46–53 Occurrence Handle10869940 Occurrence Handle1:STN:280:DC%2BD3cvisVektg%3D%3D Occurrence Handle10.1016/S1010-7940(00)00416-4
MH Yacoub PJ Kilner EJ Birks M Misfeld (1999) ArticleTitleThe aortic outflow and root: a tale of dynamism and crosstalk Ann Thorac Surg 68 S37–S43 Occurrence Handle10505990 Occurrence Handle1:STN:280:DyaK1Mvjtlyjuw%3D%3D Occurrence Handle10.1016/S0003-4975(99)00745-6
KL Yun CF Sintek AD Fletcher TA Pfeffer GS Kochamba MR Hyde JO Torpoco S Khonsari (1999) ArticleTitleAortic valve replacement with the freestyle stentiess bioprosthesis: five-year experience Circulation 100 II17–II23 Occurrence Handle10567273 Occurrence Handle1:STN:280:DC%2BD3c%2FjslSisw%3D%3D
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Yeghiazaryan, K., Skowasch, D., Bauriedel, G. et al. Could activated tissue remodeling be considered as early marker for progressive valve degeneration? Comparative analysis of checkpoint and ECM remodeling gene expression in native degenerating aortic valves and after bioprosthetic replacement. Amino Acids 32, 109–114 (2007). https://doi.org/10.1007/s00726-006-0376-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00726-006-0376-0