title: (Pro)renin receptors and angiotensin converting enzyme 2/angiotensin-(1-7)/Mas receptor axis in human aortic valve stenosis.
abstract: BACKGROUND
  There is increasing evidence that renin-angiotensin system (RAS) may play a major role in the actively regulated fibrocalcific process in aortic valve stenosis (AS), but the gene expression or function of (pro)renin receptor ((P)RR), prorenin and renin or angiotensin converting enzyme 2(ACE2)/angiotensin-(1-7)/Mas receptor axis in calcific aortic valve disease is not known.
  
  
  RESULTS
  We characterized expression of (P)RR, ACE2 and Mas receptor as well as renin, prorenin and angiotensin II type 2 (AT(2)) receptors in human aortic valves, and compared normal control valves (n = 11) with valves obtained from patients with aortic regurgitation (AR, n = 14), AR with fibrosis (n = 20) and AS (n = 61). By immunohistochemistry (P)RR positive staining was seen in the valvular endothelial cells of control and in the neovessels of stenotic valves. By RT-PCR, renin mRNA levels were 72% (P = 0.001) and prorenin mRNA levels 64% lower (P = 0.002) in stenotic aortic valves compared to control valves. ACE2, Mas receptor and AT(2)-receptor mRNA levels were 69% (P < 0.001), 58% (P = 0.008) and 75% (P = 0.001) lower, respectively, in stenotic valves. ACE2 positive staining, existing to lesser extent in stenotic aortic valves, was localized mainly to stromal area in spongiosa layer in control valves.
  
  
  CONCLUSIONS
  (P)RR, prorenin and renin are expressed in human aortic valves. We also report for the first time expression of ACE2/angiotensin-(1-7)/-Mas receptor axis in human aortic valve cusps. The downregulation of ACE2/angiotensin-(1-7)/-Mas receptor axis as well as AT(2)-receptors may promote fibrosis, proliferation and inflammation in patients with AS.
authors.affiliation: Department of Pharmacology and Toxicology, Biocenter Oulu, Institute of Biomedicine, University of Oulu, Oulu, Finland.
authors.forename: Tuomas
authors.initials: T
authors.lastname: Peltonen
authors.forename: Juha
authors.initials: J
authors.lastname: Näpänkangas
authors.forename: Pasi
authors.initials: P
authors.lastname: Ohtonen
authors.forename: Jani
authors.initials: J
authors.lastname: Aro
authors.forename: Jenni
authors.initials: J
authors.lastname: Peltonen
authors.forename: Ylermi
authors.initials: Y
authors.lastname: Soini
authors.forename: Tatu
authors.initials: T
authors.lastname: Juvonen
authors.forename: Jari
authors.initials: J
authors.lastname: Satta
authors.forename: Heikki
authors.initials: H
authors.lastname: Ruskoaho
authors.forename: Panu
authors.initials: P
authors.lastname: Taskinen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000085962:Angiotensin-Converting Enzyme 2; D001021:Aortic Valve / Q000737:chemistry* / Q000187:drug effects / Q000473:pathology; D001022:Aortic Valve Insufficiency / Q000378:metabolism; D001024:Aortic Valve Stenosis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002114:Calcinosis / Q000378:metabolism; D016022:Case-Control Studies; D005260:Female; D005355:Fibrosis; D005387:Finland; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000378:metabolism; D007703:Peptidyl-Dipeptidase A / Q000032:analysis*; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000032:analysis* / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D044139:Receptor, Angiotensin, Type 2 / Q000032:analysis; D011956:Receptors, Cell Surface / Q000032:analysis*; D043562:Receptors, G-Protein-Coupled / Q000032:analysis* / Q000235:genetics; D012083:Renin / Q000032:analysis / Q000235:genetics; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D025262:Vacuolar Proton-Translocating ATPases / Q000032:analysis*; D055815:Young Adult; D000093342:Prorenin Receptor
chemical_list: C458319:ATP6AP2 protein, human; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D044139:Receptor, Angiotensin, Type 2; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; D000085962:Angiotensin-Converting Enzyme 2; D012083:Renin; D025262:Vacuolar Proton-Translocating ATPases; D000093342:Prorenin Receptor