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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
Author(s) -
YamadaNomoto Kaori,
Yoshino Osamu,
Akiyama Ikumi,
Iwase Akira,
Ono Yosuke,
Nakamura Tomoko,
Harada Miyuki,
Nakashima Akitoshi,
Shima Tomoko,
Ushijima Akemi,
Osuga Yutaka,
Chang Russell Jeffrey,
Shimasaki Shunichi,
Saito Shigeru
Publication year - 2017
Publication title -
american journal of reproductive immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.071
H-Index - 97
eISSN - 1600-0897
pISSN - 1046-7408
DOI - 10.1111/aji.12669
Subject(s) - peripheral blood mononuclear cell , tumor necrosis factor alpha , statin , endocrinology , insulin , transforming growth factor , medicine , chemistry , microbiology and biotechnology , biology , cancer research , in vitro , biochemistry
Problem Plasminogen activator inhibitor‐1 (PAI‐1) is elevated in women with polycystic ovary syndrome (PCOS), but the regulation in granulosa cells (GCs) is unclear. Method of study 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. Results 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. Conclusion 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.