title: Gap junction blockade induces apoptosis in human endometrial stromal cells.
abstract: One of the most dynamic adult human tissues is the endometrium. Through coordinated, cyclical proliferation, differentiation, leukocyte recruitment, apoptosis, and desquamation, the uterine lining is expanded and shed monthly, unless pregnancy is established. Errors in these steps potentially cause endometrial dysfunction, abnormal uterine bleeding, failed embryonic implantation, infertility, or endometrial carcinoma. Our prior studies showed that gap junctions comprised of Gap junction alpha-1 (GJA1) protein, also known as connexin 43 (CX43), subunits are critical to endometrial stromal cell differentiation. The current studies were undertaken to explore the mechanism of endometrial dysfunction when gap junction intercellular communication (GJIC) is disrupted. Gap junction blockade by two distinct GJIC inhibitors, 18α-glycyrrhetinic acid (AGA) and octanol (OcOH), suppressed proliferation and induced apoptosis in endometrial stromal cells, as manifested by reduced biomarkers of cell viability, increased TUNEL staining, caspase-3 activation, sub-G1 chromosomal DNA complement, as well as shortened telomere length. Unexpectedly, we also observed that the chemical inhibitors blocked CX43 gene expression. Moreover, when endometrial stromal cells were induced to undergo hormonal decidualization, following a 7-day exposure to 10 nM 17β-estradiol + 100 nM progesterone + 0.5 mM dibutyryl cAMP, characteristic epithelioid changes in cell shape and secretion of prolactin were blunted in the presence of AGA or OcOH, recapitulating effects of RNA interference of CX43. Our findings indicate that endometrial stromal cell proliferation and maintenance of decidualized endometrial function are GJIC-dependent, and that disruption of gap junctions induces endometrial stromal cell apoptosis. These observations may have important implications for several common clinical endometrial pathologies.
authors.affiliation: Department of Obstetrics and Gynecology, Wake Forest School of Medicine, Winston-Salem, North California.
authors.forename: Jie
authors.initials: J
authors.lastname: Yu
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Berga
authors.forename: Wei
authors.initials: W
authors.lastname: Zou
authors.forename: He-Ying
authors.initials: HY
authors.lastname: Sun
authors.forename: Erika
authors.initials: E
authors.lastname: Johnston-MacAnanny
authors.forename: Tamer
authors.initials: T
authors.lastname: Yalcinkaya
authors.forename: Neil
authors.initials: N
authors.lastname: Sidell
authors.forename: Indrani C
authors.initials: IC
authors.lastname: Bagchi
authors.forename: Milan K
authors.initials: MK
authors.lastname: Bagchi
authors.forename: Robert N
authors.initials: RN
authors.lastname: Taylor
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D048430:Cell Shape / Q000187:drug effects / Q000502:physiology; D018031:Connexin 43 / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D004717:Endometrium / Q000166:cytology*; D005260:Female; D017629:Gap Junctions / Q000187:drug effects* / Q000502:physiology*; D006034:Glycyrrhetinic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D000442:Octanols / Q000494:pharmacology; D017154:Stromal Cells / Q000502:physiology*; D016615:Telomere / Q000187:drug effects / Q000378:metabolism
chemical_list: D018031:Connexin 43; D000442:Octanols; C119129:18alpha-glycyrrhetinic acid; D006034:Glycyrrhetinic Acid