Summary.
The mechanisms underlying aortic valve degeneration are largely unknown. Cardiac tissue responds to a variety of stimuli by hypertrophic growth. Molecular mechanisms resulting in the hypertrophic response indicate similarity and overlap with those involved in both cell growth and death. We hypothesized cell cycle control to be the key event in progression regulation of heart valve degeneration followed by tissue mineralization. Human post-operative tissue samples of native non-rheumatic stenosed aortic valves were categorized according to absence (group 1) or presence of calcification (group 2). The samples were ex vivo examined for cell density and presence of macrophage (CD68), as well as expression of two checkpoint genes, p21WAF1/CIP1 and 14-3-3 σ, arresting the G1 and G2 cell cycle phases, respectively. Expression rates were measured by “Real-Time”-PCR on transcriptional level. Target protein expression was measured and their co-localization in different kinds of valvular cells was tested using immunohistochemical analysis. Whereas macrophages were localized predominantly in sub-endothelial layer of valvular fibrosis, p21WAF1/CIP1 and 14-3-3 σ expression was observed also in the valvular spongiosa co-localized with alpha-actin positive cells. Significantly higher cell density and inflammation grade were observed in group 2 versus group 1. Accordingly, p21WAF1/CIP1 and 14-3-3 σ expression was several fold higher in group 1 versus group 2 on both transcription and translation levels. The present findings on degenerated aortic valves show that increased cell density accompanied with consequent calcification might be attributed to the down-regulation of both G1 and G2 checkpoint genes.
Similar content being viewed by others
References
S Akli S Zhan M Abdellatif MD Schneider (1999) ArticleTitleE1A can provoke G1 exit that is refractory to p21 and independent of activating cdk2 Circ Res 85 319–328 Occurrence Handle10455060 Occurrence Handle1:CAS:528:DyaK1MXltlehurw%3D
MDH Bär J Kreuzer A Cojoc L Jahn (2003) ArticleTitleUpregulation of embryonic transcription factors in right ventricular hypertrophy Basic Res Cardiol 98 285–294 Occurrence Handle12955401 Occurrence Handle10.1007/s00395-003-0410-2 Occurrence Handle1:CAS:528:DC%2BD3sXot1Cksr4%3D
K Bostrom KE Watson S Horn C Wortham IM Herman LL Demer (1993) ArticleTitleBone morphogenetic protein expression in human atherosclerotic lesions J Clin Invest 91 1800–1809 Occurrence Handle8473518 Occurrence Handle1:CAS:528:DyaK3sXktVKhs7w%3D
PB Burton MH Yacoub PJ Barton (1999) ArticleTitleCyclin-dependent kinase inhibitor expression in human heart failure. A comparison with fetal development Eur Heart J 20 604–611 Occurrence Handle10337545 Occurrence Handle1:STN:280:DyaK1M3mvFyguw%3D%3D Occurrence Handle10.1053/euhj.1998.1231
F Cipollone C Prontera B Pini M Marini M Fazia D De Cesare A Iezzi S Ucchino G Boccoli V Saba F Chiarelli F Cuccurullo A Mezzetti (2001) ArticleTitleOverexpression of functionally coupled cyclooxygenase-2 and prostaglandin E synthase in symptomatic atherosclerotic plaques as a basis of prostaglandin E(2)-dependent plaque instability Circulation 104 921–927 Occurrence Handle11514380 Occurrence Handle1:CAS:528:DC%2BD3MXmvFKms7o%3D
NG Frangogiannis CW Smith ML Entman (2002) ArticleTitleThe inflammatory response in myocardial infarction Cardiovasc Res 53 31–47 Occurrence Handle11744011 Occurrence Handle1:CAS:528:DC%2BD3MXptVahsb0%3D Occurrence Handle10.1016/S0008-6363(01)00434-5
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
CA Heid J Stevens KJ Livak PM Williams (1996) ArticleTitleReal time quantitative PCR Genome Res 6 986–994 Occurrence Handle8908518 Occurrence Handle1:CAS:528:DyaK28XmsVWru7w%3D
B Jian PL Jones Q Li ER Mohler Suffix3rd FJ Schoen RJ Levy (2001) ArticleTitleMatrix metalloproteinase-2 is associated with tenascin-C in calcific aortic stenosis Am J Pathol 159 321–327 Occurrence Handle11438479 Occurrence Handle1:CAS:528:DC%2BD3MXlslamu7g%3D
KM Kim (1995) ArticleTitleApoptosis and calcification Scanning Microsc 9 1137–1178 Occurrence Handle8819895 Occurrence Handle1:CAS:528:DyaK28XhtFyrsr4%3D
F Limana K Urbanek S Chimenti F Quaini A Leri J Kajstura B Nadal-Ginard S Izumo P Anversa (2002) ArticleTitlebcl-2 overexpression promotes myocyte proliferation Proc Natl Acad Sci USA 99 6257–6262 Occurrence Handle11983915 Occurrence Handle1:CAS:528:DC%2BD38XjslWnsbw%3D Occurrence Handle10.1073/pnas.092672899
ZP Liu EN Olson (2002) ArticleTitleSuppression of proliferation and cardiomyocyte hypertrophy by CHAMP, a cardiac-specific RNA helicase Proc Natl Acad Sci USA 99 2043–2048 Occurrence Handle11854500 Occurrence Handle1:CAS:528:DC%2BD38XitVSrsbo%3D Occurrence Handle10.1073/pnas.261708699
E Lutgens ED de Muinck PJ Kitslaar JH Tordoir HJ Wellens MJ Daemen (1999) ArticleTitleBiphasic pattern of cell turnover characterizes the progression from fatty streaks to ruptured human atherosclerotic plaques Cardiovasc Res 41 473–479 Occurrence Handle10341847 Occurrence Handle1:CAS:528:DyaK1MXht12qsro%3D Occurrence Handle10.1016/S0008-6363(98)00311-3
MJ Mann GH Gibbons PS Tsao HE von der Leyen JP Cooke R Buitrago R Kernoff VJ Dzau (1997) ArticleTitleCell cycle inhibition preserves endothelial function in genetically engineered rabbit vein grafts J Clin Invest 99 1295–1301 Occurrence Handle9077539 Occurrence Handle1:CAS:528:DyaK2sXitVWhu7k%3D Occurrence Handle10.1172/JCI119288
I Mercier F Colombo S Mader A Calderone (2002) ArticleTitleOvarian hormones induce TGF-beta(3) and fibronectin mRNAs but exhibit a disparate action on cardiac fibroblast proliferation Cardiovasc Res 53 728–739 Occurrence Handle11861043 Occurrence Handle1:CAS:528:DC%2BD38Xhtleqsbw%3D Occurrence Handle10.1016/S0008-6363(01)00525-9
B Nadal-Ginard (2001) ArticleTitleGeneration of new cardiomyocytes in the adult heart: prospects of myocardial regeneration as an alternative to cardiac transplantation Rev Esp Cardiol 54 543–550 Occurrence Handle11412743 Occurrence Handle1:STN:280:DC%2BD3MvhslKjtA%3D%3D
T Samuel HO Weber P Rauch B Verdoodt JT Eppel A McShea H Hermeking JO Funk (2001) ArticleTitleThe G2/M regulator 14-3-3 sigma prevents apoptosis through sequestration of Bax J Biol Chem 276 45201–45206 Occurrence Handle11574543 Occurrence Handle1:CAS:528:DC%2BD3MXovFensLk%3D Occurrence Handle10.1074/jbc.M106427200
DB Sanders K Hunter Y Wu C Jablonowski JJ Bahl DF Larson (2001) ArticleTitleModulation of the inflammatory response in the cardiomyocyte and macrophage J Extra Corpor Technol 33 167–174
HH Schmidt U Walter (1994) ArticleTitleNO at work Cell 78 919–925 Occurrence Handle7923361 Occurrence Handle1:CAS:528:DyaK2cXmt1Kquro%3D Occurrence Handle10.1016/0092-8674(94)90267-4
FJ Schoen (2005) ArticleTitleCardiac valves and valvular pathology: update on function, disease, repair, and replacement Cardiovasc Pathol 14 189–194 Occurrence Handle16009317 Occurrence Handle10.1016/j.carpath.2005.03.005
CJ Sherr (1994) ArticleTitleG1 phase progression: cycling on cue Cell 79 551–555 Occurrence Handle7954821 Occurrence Handle1:CAS:528:DyaK2MXit1Glu7o%3D Occurrence Handle10.1016/0092-8674(94)90540-1
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
M Tamamori H Ito M Hiroe Y Terada F Marumo MA Ikeda (1998) ArticleTitleEssential roles for G1 cyclin-dependent kinase activity in development of cardiomyocyte hypertrophy Am J Physiol 275 H2036–H2040 Occurrence Handle9843802 Occurrence Handle1:CAS:528:DyaK1MXht1Oksw%3D%3D
R von Harsdorf L Hauck F Mehrhof U Wegenka MC Cardoso R Dietz (1999) ArticleTitleE2F-1 overexpression in cardiomyocytes induces downregulation of p21CIP1 and p27KIP1 and release of active cyclin-dependent kinases in the presence of insulin-like growth factor I Circ Res 85 128–136 Occurrence Handle10417394 Occurrence Handle1:CAS:528:DyaK1MXkslSktr0%3D
JC Zhuang GN Wogan (1997) ArticleTitleGrowth and viability of macrophages continuously stimulated to produce nitric oxide Proc Natl Acad Sci USA 94 11875–11880 Occurrence Handle9342330 Occurrence Handle1:CAS:528:DyaK2sXntFSmsrY%3D Occurrence Handle10.1073/pnas.94.22.11875
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Golubnitschaja, O., Yeghiazaryan, K., Skowasch, D. et al. p21WAF1/CIP1 and 14-3-3 σ gene expression in degenerated aortic valves: A link between cell cycle checkpoints and calcification. Amino Acids 31, 309–316 (2006). https://doi.org/10.1007/s00726-006-0365-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00726-006-0365-3