PAI-1 in granulosa cells is suppressed directly by statin and indirectly by suppressing TGF-β and TNF-α in mononuclear cells by insulin-sensitizing drugs.
Plasminogen activator inhibitor-1 (PAI-1) is elevated in women with polycystic ovary syndrome (PCOS), but the regulation in granulosa cells (GCs) is unclear.



PAI-1 expression in PCOS ovaries was investigated immunohistologically. PAI-1 expressions in HGrC1, a human GC cell line, were investigated at mRNA and activity levels. The expressions of TGF-β and TNF-α in peritoneal fluid mononuclear cells (PFMCs) were measured with quantitative PCR.



Little PAI-1 expression is observed in healthy GCs, whereas GCs of PCOS and atretic follicle exhibit distinct expression in vivo. In vitro study using HGrC1 shows that TGF-β and TNF-α increase PAI-1 mRNA and its activity, and both together exhibit a synergistic effect. The expression of PAI-1 mRNA is suppressed by simvastatin. Moreover, insulin-sensitizing drugs (metformin, pioglitazone, and rosiglitazone) suppress LPS-induced TGF-β and TNF-α mRNA expression in PFMC.



Statin and insulin-sensitizing drugs may provide a potential therapy for PCOS via down-regulation of PAI-1 expression in GCs and down-regulation of TGF-β and TNF-α expression in PFMC, respectively.
Department of Obstetrics and Gynecology, University of Toyama, Toyama, Japan.
Kaori
K
Yamada-Nomoto
Department of Obstetrics and Gynecology, University of Toyama, Toyama, Japan.
Osamu
O
Yoshino
Department of Obstetrics and Gynecology, University of Tokyo, Tokyo, Japan.
Ikumi
I
Akiyama
Department of Obstetrics and Gynecology, Nagoya University, Nagoya, Japan.
Akira
A
Iwase
Department of Obstetrics and Gynecology, University of Toyama, Toyama, Japan.
Yosuke
Y
Ono
Department of Obstetrics and Gynecology, Nagoya University, Nagoya, Japan.
Tomoko
T
Nakamura
Department of Obstetrics and Gynecology, University of Tokyo, Tokyo, Japan.
Miyuki
M
Harada
Department of Obstetrics and Gynecology, University of Toyama, Toyama, Japan.
Akitoshi
A
Nakashima
Department of Obstetrics and Gynecology, University of Toyama, Toyama, Japan.
Tomoko
T
Shima
Department of Obstetrics and Gynecology, University of Toyama, Toyama, Japan.
Akemi
A
Ushijima
Department of Obstetrics and Gynecology, University of Tokyo, Tokyo, Japan.
Yutaka
Y
Osuga
Department of Reproductive Medicine, University of California San Diego, La Jolla, CA, USA.
Russell Jeffrey
RJ
Chang
Department of Reproductive Medicine, University of California San Diego, La Jolla, CA, USA.
Shunichi
S
Shimasaki
Department of Obstetrics and Gynecology, University of Toyama, Toyama, Japan.
Shigeru
0000-0002-8940-3708
S
Saito
D001202:Ascitic Fluid / Q000166:cytology; D002460:Cell Line; D005260:Female; D006107:Granulosa Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000378:metabolism; D008070:Lipopolysaccharides; D006080:Ovarian Follicle / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism*; D011085:Polycystic Ovary Syndrome / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D019821:Simvastatin / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007004:Hypoglycemic Agents; D008070:Lipopolysaccharides; D017395:Plasminogen Activator Inhibitor 1; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; C051321:SERPINE1 protein, human; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D019821:Simvastatin
PAI-1; granulosa cell; polycystic ovary syndrome; statin