title: 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.
abstract: OBJECTIVE
  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.
  
  
  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 p21(waf1/cip1), MT1-MMP, MMP-2, MMP-9 and TIMP-1 were measured. The specificity was controlled by restriction analysis of PCR products.
  
  
  CONCLUSIONS
  According to the abundant expression of p21(waf1/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.
authors.affiliation: Department of Radiology, Friedrich-Wilhelms-University of Bonn, Bonn, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Yeghiazaryan
authors.forename: D
authors.initials: D
authors.lastname: Skowasch
authors.forename: G
authors.initials: G
authors.lastname: Bauriedel
authors.forename: H
authors.initials: H
authors.lastname: Schild
authors.forename: O
authors.initials: O
authors.lastname: Golubnitschaja
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001021:Aortic Valve / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D001024:Aortic Valve Stenosis / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D001705:Bioprosthesis; D002114:Calcinosis / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D009202:Cardiomyopathies / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis; D005109:Extracellular Matrix / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D006350:Heart Valve Prosthesis; D006801:Humans; D008297:Male; D020782:Matrix Metalloproteinases / Q000096:biosynthesis; D008875:Middle Aged; D013312:Stress, Physiological / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis; D015533:Transcriptional Activation
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D019715:Tissue Inhibitor of Metalloproteinase-1; D020782:Matrix Metalloproteinases