Impaired migration of trophoblast cells caused by simvastatin is associated with decreased membrane IGF-I receptor, MMP2 activity and HSP27 expression.
BACKGROUND
Statins inhibit 3-hydroxy-3-methylglutaryl coenzyme-A reductase, the rate-limiting enzyme of the mevalonate pathway, and are used successfully in the treatment of hypercholesterolaemia. Statins are contraindicated during pregnancy. Lately, we have shown that simvastatin has adverse affects on human first trimester placental explants' proliferation and migration. The objective of the present study was to investigate the molecules involved in mediating simvastatin's effect on trophoblast cell migration. We hypothesized that simvastatin attenuates insuline-like growth factor-I (IGF-I) receptor expression (involved in trophoblast motility), matrix metalloproteinase (MMP) activities, and heat shock protein 27 (HSP27) levels (whose mRNA is actively transcribed during trophoblast differentiation) in trophoblast cells thus consequently effecting their migration.


METHODS
Human placental explants were cultured above a matrigel with/without simvastatin (10 microM) for 5 days. In this model, trophoblast migrates from the villi into the matrigel. Western-blot and immunohistochemistry served for analysing HSP27 expression. Immunohistochemistry was used for assessing IGF-I receptor localization. MMPs activity was assayed by gel zymography.


RESULTS
Simvastatin reduced IGF-I receptor membranal expression, MMP2 activity and HSP27 expression in trophoblast cells (P < 0.05).


CONCLUSIONS
The inhibitory effect of simvastatin on trophoblast cell migration is associated with a significant decrease in the tested molecules, which probably contributes to the impaired migration.
Tartakover-Matalon
S
S
Oncogenetic Laboratory, Meir Medical Centre, Kfar-Saba, Israel. matalon.shelly@clalit.org.il
Cherepnin
N
N
Kuchuk
M
M
Drucker
L
L
Kenis
I
I
Fishman
A
A
Pomeranz
M
M
Lishner
M
M
D015153:Blotting, Western; D002465:Cell Movement; D003094:Collagen / Q000494:pharmacology; D004338:Drug Combinations; D005260:Female; D005865:Gestational Age; D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins / Q000096:biosynthesis*; D006801:Humans; D007797:Laminin / Q000494:pharmacology; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis*; D018832:Molecular Chaperones; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D011509:Proteoglycans / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000096:biosynthesis*; D019821:Simvastatin / Q000378:metabolism / Q000494:pharmacology*; D014327:Trophoblasts / Q000166:cytology* / Q000378:metabolism*
D004338:Drug Combinations; D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D007797:Laminin; D018832:Molecular Chaperones; D009363:Neoplasm Proteins; D011509:Proteoglycans; D012333:RNA, Messenger; C059485:matrigel; D003094:Collagen; D019821:Simvastatin; D017526:Receptor, IGF Type 1; D020778:Matrix Metalloproteinase 2