title: Potential pathological roles for oxidized low-density lipoprotein and scavenger receptors SR-AI, CD36, and LOX-1 in aortic valve stenosis.
abstract: OBJECTIVE
  To clarify the potential mechanisms by which oxidized low-density lipoprotein (oxLDL) could contribute to the progression of aortic valve stenosis (AVS).
  
  
  METHODS
  We investigated a total of 46 stenotic and 20 control human aortic valves. The mRNA expression levels of scavenger receptor class A type 1 (SR-A1), CD36, Lectin-like oxidized LDL receptor-1 (LOX-1), and scavenger receptor class B type 1 (SR-B1) were studied using qPCR. Their cellular distribution in the valves was assessed by immunohistochemistry, and the potential effects of oxLDL were studied in cultured myofibroblasts isolated from the aortic valves.
  
  
  RESULTS
  In AVS, the proinflammatory SR-A1 and the angiogenic LOX-1 were upregulated (p = 0.003 and p = 0.002), whereas the antiangiogenic CD36 was downregulated (p = 0.02). The expression of the atheroprotective SR-B1 remained unchanged. Immunohistochemistry revealed that SR-A1 was expressed by macrophages, whereas the expression of CD36 and LOX-1 was confined to myofibroblasts and endothelial cells in the diseased valves. In cultured valvular myofibroblasts, mast cell-derived components and TNF-α induced LOX-1 expression (p = 0.05 and p < 0.001), whereas oxLDL promoted the expression of proinflammatory cytokines. Furthermore, the expression of osteoprotegerin, an inhibitor of valvular calcification, decreased in response to oxLDL. Finally, myofibroblasts derived from stenotic valves accumulated more DiI-labeled oxLDL than myofibroblasts derived from macroscopically healthy valves (p = 0.035), so revealing enhanced foam cell-forming potential of myofibroblasts in the diseased valves.
  
  
  CONCLUSIONS
  This study unveils the presence of SR-A1, CD36, and LOX-1 in aortic valves and suggests potential mechanisms by which they may contribute to the pathological angiogenesis, inflammation, calcification, and lipid accumulation in AVS.
authors.affiliation: Wihuri Research Institute, Helsinki, Finland.
authors.forename: Suvi
authors.initials: S
authors.lastname: Syväranta
authors.affiliation: Wihuri Research Institute, Helsinki, Finland.
authors.forename: Mervi
authors.initials: M
authors.lastname: Alanne-Kinnunen
authors.affiliation: Wihuri Research Institute, Helsinki, Finland.
authors.forename: Katariina
authors.initials: K
authors.lastname: Oörni
authors.affiliation: Wihuri Research Institute, Helsinki, Finland.
authors.forename: Riina
authors.initials: R
authors.lastname: Oksjoki
authors.affiliation: Division of Cardiology, Heart and Lung Center, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Markku
authors.initials: M
authors.lastname: Kupari
authors.affiliation: Wihuri Research Institute, Helsinki, Finland.
authors.forename: Petri T
authors.initials: PT
authors.lastname: Kovanen
authors.affiliation: Wihuri Research Institute, Helsinki, Finland. Electronic address: satu.helske@wri.fi.
authors.forename: Satu
authors.initials: S
authors.lastname: Helske-Suihko
mesh_terms: D001024:Aortic Valve Stenosis / Q000503:physiopathology*; D018955:CD36 Antigens / Q000378:metabolism*; D002478:Cells, Cultured; D018450:Disease Progression; D015536:Down-Regulation; D042783:Endothelial Cells / Q000378:metabolism; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism*; D058628:Myofibroblasts / Q000378:metabolism; D053244:Osteoprotegerin / Q000096:biosynthesis; D051117:Scavenger Receptors, Class A / Q000378:metabolism*; D051127:Scavenger Receptors, Class E / Q000096:biosynthesis / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D018955:CD36 Antigens; D008077:Lipoproteins, LDL; C495137:OLR1 protein, human; D053244:Osteoprotegerin; D051117:Scavenger Receptors, Class A; D051127:Scavenger Receptors, Class E; C099252:oxidized low density lipoprotein
keywords: Angiogenesis; Aortic valve stenosis; Oxidized low-density lipoprotein; Scavenger receptors; Valvular interstitial cells