Non-lesional vitiliginous melanocytes are not characterized by an increased proneness to nitric oxide-induced apoptosis.
Nitric oxide (NO) is a reactive endogenous molecule with multiple functions including inflammation and immunity. NO stimulates melanogenesis by activating soluble guanylyl cyclase (sGC) resulting in increases in intracellular guanosine 3',5'-cyclic monophosphate (cGMP). In vitro experiments showed that NO could inhibit the de novo attachment of melanocytes to extracellular matrix (ECM) suggesting that NO-induced aberrant perturbation of melanocyte-ECM interaction could be a reason for melanocyte loss in vitiliginous lesions. Here, we examined whether there might be differences between normal melanocytes and vitiliginous melanocytes (VMs) with respect to NO-induced detachment from ECM and whether cGMP is involved. We used the direct NO donor (Z)-1-[N-(3-ammoniopropyl)-N-(n-propyl)amino]diazen-1-ium-1,2-diolate and the peroxynitrite donor 3-morpholino-sydnonimine for the present studies. These donors induced detachment of both normal melanocytes and non-lesional VMs in a time- and concentration-dependent manner with comparable susceptibility and similar expression profile of sGC. Treatment of melanocytes with caspase inhibitors reduced cell detachment, indicating that a major part of the detachment is due to apoptosis. The NO-induced detachment but not apoptosis was partly inhibited in the presence of sGC and cGMP-dependent protein kinase inhibitors. In addition, the membrane-permeable cGMP analog 8-(4-chlorophenyethio/guanosine-3',5'-cyclic monophosphate (PCPT) cGMP was not able to induce apoptosis in melanocytes, suggesting that NO-induced detachment of melanocytes via apoptosis is cGMP-independent. The present results also indicate that there are no apparent differences between NO-induced detachment of non-lesional vitiliginous and normal melanocytes from ECM.
Ivanova
Krassimira
K
Institute of Aerospace Medicine, German Aerospace Center, Cologne, Germany. krassimira.ivanova@dir.de
van den Wijngaard
Rene
R
Gerzer
Rupert
R
Lamers
Wouter H
WH
Das
Pranab K
PK
D017209:Apoptosis; D001384:Azetidines / Q000494:pharmacology; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005109:Extracellular Matrix / Q000378:metabolism; D005353:Fibronectins / Q000737:chemistry; D006162:Guanylate Cyclase / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008544:Melanocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D009569:Nitric Oxide / Q000737:chemistry / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014226:Triazenes / Q000737:chemistry; D014820:Vitiligo / Q000378:metabolism* / Q000473:pathology
C111679:1-(N-(3-ammoniopropyl)-N-(n-propyl)amino)diazen-1-ium-1,2-diolate; C105351:1-hydroxy-2-oxo-3,3-bis(2-aminoethyl)-1-triazene; D001384:Azetidines; D005353:Fibronectins; D020030:Nitric Oxide Donors; D012333:RNA, Messenger; D014226:Triazenes; D009569:Nitric Oxide; D006162:Guanylate Cyclase; D006152:Cyclic GMP