title: Upregulation of the 5-lipoxygenase pathway in human aortic valves correlates with severity of stenosis and leads to leukotriene-induced effects on valvular myofibroblasts.
abstract: BACKGROUND
  The development of aortic valve stenosis is not only associated with calcification and extracellular matrix remodeling, but also with inflammation. The aim of this study was to determine the role of proinflammatory signaling through the leukotriene (LT) pathway in aortic stenosis.
  
  
  RESULTS
  After macroscopic dissection of surgically removed human aortic valves, RNA was extracted from 311 preparations derived from 68 patients to differentiate normal, thickened, and calcified areas from each cusp. Subsequently, quantitative polymerase chain reaction analysis was used to correlate gene expression patterns with preoperative echocardiographic parameters. The messenger RNA levels of the LT-forming enzyme 5-lipoxygenase increased 1.6- and 2.2-fold in thickened and calcified tissue, respectively, compared with normal areas of the same valves. In thickened tissues, messenger RNA levels for 5-lipoxygenase (r= -0.35; P=0.03), its activating protein (5-lipoxygenase activating protein; r= -0.39; P=0.02), and LTA(4) hydrolase (r= -0.48; P=0.01) correlated inversely with the velocity-time integral ratio. In addition, leukotriene A(4) hydrolase transcripts correlated inversely with aortic valve area, indexed for body surface area (r= -0.52; P=0.007). Immunohistochemical stainings revealed LT receptor expression on valvular myofibroblasts. In primary cultures of human myofibroblasts derived from stenotic aortic valves, Leukotriene C(4) (LTC(4)) increased intracellular calcium, enhanced reactive oxygen species production, reduced the mitochondrial membrane potential, and led to morphological cell cytoplasm changes and calcification.
  
  
  CONCLUSIONS
  The upregulation of the LT pathway in human aortic valve stenosis and its correlation with clinical stenosis severity, taken together with the potentially detrimental LT-induced effects on valvular myofibroblasts, suggests one possible role of inflammation in the development of aortic stenosis.
authors.affiliation: Center for Molecular Medicine, CMM L8:03, Karolinska University Hospital, Stockholm, Sweden. edit.nagy@karolinska.se
authors.forename: Edit
authors.initials: E
authors.lastname: Nagy
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Andersson
authors.forename: Kenneth
authors.initials: K
authors.lastname: Caidahl
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Eriksson
authors.forename: Per
authors.initials: P
authors.lastname: Eriksson
authors.forename: Anders
authors.initials: A
authors.lastname: Franco-Cereceda
authors.forename: Göran K
authors.initials: GK
authors.lastname: Hansson
authors.forename: Magnus
authors.initials: M
authors.lastname: Bäck
mesh_terms: D000368:Aged; D001021:Aortic Valve / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D001024:Aortic Valve Stenosis / Q000175:diagnosis / Q000276:immunology / Q000503:physiopathology*; D001094:Arachidonate 5-Lipoxygenase / Q000235:genetics* / Q000378:metabolism*; D002478:Cells, Cultured; D004452:Echocardiography; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000201:enzymology; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D017997:Leukotriene C4 / Q000276:immunology / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D008943:Mitral Valve / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D009205:Myocarditis / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018077:Receptors, Leukotriene / Q000235:genetics / Q000378:metabolism; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000276:immunology*; D014261:Tricuspid Valve / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D015854:Up-Regulation / Q000502:physiology
chemical_list: D018077:Receptors, Leukotriene; D017997:Leukotriene C4; D001094:Arachidonate 5-Lipoxygenase