title: Expression of smooth muscle cell markers and co-activators in calcified aortic valves.
abstract: OBJECTIVE
  Similar risk factors and mediators are involved in calcific aortic stenosis (CAS) and atherosclerosis. Since normal valves harbour a low percentage of smooth muscle cells (SMCs), we hypothesize that the SMC phenotype participates in the pathogenesis of CAS.
  
  
  RESULTS
  We analysed 12 normal and 22 calcified aortic valves for SMC markers and the expression of co-activators of SMC gene expression, myocardin and myocardin-related transcription factors (MRTF-A/B). Transforming growth factor β (TGFβ1) was used to upregulate SMC markers and co-activators in valve interstitial cells (VICs) and transmission electron microscopy (TEM) was used to detect the presence of SMC in atypical regions of the valve leaflets. Smooth muscle cell markers and co-activators, myocardin, MRTF-A, and MRTF-B, demonstrated an increased incidence and aberrant expression around calcified nodules in all 22 calcified valves as well as in surface and microvessel endothelial cells. Smooth muscle cell markers and MRTF-A were significantly increased in calcified valves. Transforming growth factor β1 (TGFβ1) (10 ng/mL) was able to significantly upregulate the expression of some SMC markers and MRTF-A in VICs. Transmission electron microscopy of the fibrosa layer of calcified valves demonstrated the presence of bundles of SMCs and smooth muscle-derived foam cells.
  
  
  CONCLUSIONS
  Smooth muscle cell markers and co-activators, myocardin and MRTFs, were aberrantly expressed in calcified valves. Transforming growth factor β1 was able to significantly upregulate SMC markers and MRTF-A in VICs. Transmission electron microscopy unequivocally identified the presence of SMCs in calcified regions of valve leaflets. These findings provide evidence that the SMC phenotype plays a role in the development of CAS.
authors.affiliation: Heart Science Centre, Imperial College, Harefield Hospital, Harefield, Middlesex UB9 6JH, UK QCRC, Qatar Cardiovascular Research Centre, Qatar Foundation, Qatar n.latif@imperial.ac.uk.
authors.forename: Najma
authors.initials: N
authors.lastname: Latif
authors.affiliation: Heart Science Centre, Imperial College, Harefield Hospital, Harefield, Middlesex UB9 6JH, UK QCRC, Qatar Cardiovascular Research Centre, Qatar Foundation, Qatar.
authors.forename: Padmini
authors.initials: P
authors.lastname: Sarathchandra
authors.affiliation: Heart Science Centre, Imperial College, Harefield Hospital, Harefield, Middlesex UB9 6JH, UK QCRC, Qatar Cardiovascular Research Centre, Qatar Foundation, Qatar.
authors.forename: Adrian H
authors.initials: AH
authors.lastname: Chester
authors.affiliation: Heart Science Centre, Imperial College, Harefield Hospital, Harefield, Middlesex UB9 6JH, UK QCRC, Qatar Cardiovascular Research Centre, Qatar Foundation, Qatar.
authors.forename: Magdi H
authors.initials: MH
authors.lastname: Yacoub
mesh_terms: D000293:Adolescent; D000328:Adult; D001021:Aortic Valve / Q000378:metabolism / Q000473:pathology*; D001024:Aortic Valve Stenosis / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism*; D002114:Calcinosis / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D005260:Female; D005487:Foam Cells / Q000378:metabolism; D006801:Humans; D008297:Male; D008840:Microfilament Proteins / Q000378:metabolism; D046529:Microscopy, Electron, Transmission; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D010641:Phenotype; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology; D055815:Young Adult; D000096985:Calponins; D000099251:Myocardin
chemical_list: D015415:Biomarkers; D002135:Calcium-Binding Proteins; D008840:Microfilament Proteins; D009687:Nuclear Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D000096985:Calponins; D000099251:Myocardin
keywords: Calcification; Cardiac; Human; Smooth muscle cells; Valve