title: Neurotrophin 3 upregulates proliferation and collagen production in human aortic valve interstitial cells: a potential role in aortic valve sclerosis.
abstract: Calcific aortic valve disease (CAVD) is a leading cardiovascular disorder in the elderly. Diseased aortic valves are characterized by sclerosis (fibrosis) and nodular calcification. Sclerosis, an early pathological change, is caused by aortic valve interstitial cell (AVIC) proliferation and overproduction of extracellular matrix (ECM) proteins. However, the mechanism of aortic valve sclerosis remains unclear. Recently, we observed that diseased human aortic valves overexpress growth factor neurotrophin 3 (NT3). In the present study, we tested the hypothesis that NT3 is a profibrogenic factor to human AVICs. AVICs isolated from normal human aortic valves were cultured in M199 growth medium and treated with recombinant human NT3 (0.10 µg/ml). An exposure to NT3 induced AVIC proliferation, upregulated the production of collagen and matrix metalloproteinase (MMP), and augmented collagen deposition. These changes were abolished by inhibition of the Trk receptors. NT3 induced Akt phosphorylation and increased cyclin D1 protein levels in a Trk receptor-dependent fashion. Inhibition of Akt abrogated the effect of NT3 on cyclin D1 production. Furthermore, inhibition of either Akt or cyclin D1 suppressed NT3-induced cellular proliferation and MMP-9 and collagen production, as well as collagen deposition. Thus, NT3 upregulates cellular proliferation, ECM protein production, and collagen deposition in human AVICs. It exerts these effects through the Trk-Akt-cyclin D1 cascade. NT3 is a profibrogenic mediator in human aortic valve, and overproduction of NT3 by aortic valve tissue may contribute to the mechanism of valvular sclerosis.
authors.affiliation: Department of Surgery, University of Colorado Denver, Aurora, Colorado.
authors.forename: Qingzhou
authors.initials: Q
authors.lastname: Yao
authors.affiliation: Department of Surgery, University of Colorado Denver, Aurora, Colorado.
authors.forename: Rui
authors.initials: R
authors.lastname: Song
authors.affiliation: Department of Surgery, University of Colorado Denver, Aurora, Colorado.
authors.forename: Lihua
authors.initials: L
authors.lastname: Ao
authors.affiliation: Department of Surgery, University of Colorado Denver, Aurora, Colorado.
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Cleveland
authors.affiliation: Department of Surgery, University of Colorado Denver, Aurora, Colorado.
authors.forename: David A
authors.initials: DA
authors.lastname: Fullerton
authors.affiliation: Department of Surgery, University of Colorado Denver, Aurora, Colorado xianzhong.meng@ucdenver.edu.
authors.forename: Xianzhong
authors.initials: X
authors.lastname: Meng
mesh_terms: D000368:Aged; D001021:Aortic Valve / Q000378:metabolism / Q000473:pathology* / Q000601:surgery; D001024:Aortic Valve Stenosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D002114:Calcinosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D016022:Case-Control Studies; D049109:Cell Proliferation / Q000187:drug effects; D003094:Collagen / Q000096:biosynthesis / Q000235:genetics*; D019938:Cyclin D1 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D020782:Matrix Metalloproteinases / Q000096:biosynthesis / Q000235:genetics*; D008875:Middle Aged; D058628:Myofibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D020933:Neurotrophin 3 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D061251:Primary Cell Culture; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D020917:Receptor, trkA / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D012598:Sclerosis; D015398:Signal Transduction; D065467:Transcatheter Aortic Valve Replacement
chemical_list: D020933:Neurotrophin 3; D047428:Protein Kinase Inhibitors; D019938:Cyclin D1; D003094:Collagen; D020917:Receptor, trkA; D051057:Proto-Oncogene Proteins c-akt; D020782:Matrix Metalloproteinases
keywords: AVIC; Akt; Trk; fibrogenic response; neurotrophin 3