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          Institute: MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut)     Collection: Yearbook_2014     Display Documents



ID: 682146.0, MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut) / Yearbook_2014
Hyperhomocysteinemia is detrimental to pregnancy in mice and is associated with preterm birth
Authors:Sonne, S. R.; Bhalla, V. K.; Barman, S. A.; White, R. E.; Zhu, S.; Newman, T. M.; Prasad, P. D.; Smith, S. B.; Offermanns, S.; Ganapathy, V.
Date of Publication (YYYY-MM-DD):2013-08
Journal Abbrev.:Biochim Biophys Acta
Volume:1832
Issue / Number:8
Start Page:1149
End Page:1158
Audience:Not Specified
Abstract / Description:Elevated levels of homocysteine produce detrimental effects in humans but its role in preterm birth is not known. Here we used a mouse model of hyperhomocysteinemia to examine the relevance of homocysteine to preterm birth. The mouse carries a heterozygous deletion of cystathionine beta-synthase (Cbs(+/-)). Gestational period was monitored in wild type and Cbs(+/-) female mice. Mouse uterine and placental tissues, human primary trophoblast cells, and human myometrial and placental cell lines were used to determine the influence of homocysteine on expression of specific genes in vitro. The activity of BKCa channel in the myometrial cell line was monitored using the patch-clamp technique. We found that hyperhomocysteinemia had detrimental effects on pregnancy and induced preterm birth in mice. Homocysteine increased the expression of oxytocin receptor and Cox-2 as well as PGE2 production in uterus and placenta, and initiated premature uterine contraction. A Cox-2 inhibitor reversed these effects. Gpr109a, a receptor for niacin, induced Cox-2 in uterus. Homocysteine upregulated GPR109A and suppressed BKCa channel activity in human myometrial cells. Deletion of Gpr109a in Cbs(+/-) mice reversed premature birth. We conclude that hyperhomocysteinemia causes preterm birth in mice through upregulation of the Gpr109a/Cox-2/PGE2 axis and that pharmacological blockade of Gpr109a may have potential in prevention of preterm birth.
Free Keywords:Animals; Cell Line; Cyclooxygenase 2/genetics/metabolism; Cyclooxygenase 2 Inhibitors/pharmacology; Cystathionine beta-Synthase/genetics/metabolism; Dinoprostone/genetics/metabolism; Female; Homocysteine/*blood/genetics/metabolism; Humans; Hyperhomocysteinemia/genetics/metabolism/*physiopathology; Large-Conductance Calcium-Activated Potassium Channel alpha; Subunits/genetics/metabolism; Mice; Mice, Inbred C57BL; Muscle Contraction; Myometrium/metabolism/physiopathology; Placenta/metabolism/physiopathology; Pregnancy; Pregnancy Complications/*blood/genetics/physiopathology; Premature Birth/*blood/genetics/physiopathology; Receptors, Nicotinic/genetics/metabolism; Receptors, Oxytocin/genetics/metabolism; Trophoblasts/metabolism; Up-Regulation; Uterus/metabolism/pathology/physiopathology
External Publication Status:published
Document Type:Article
Communicated by:Svea Hümmer
Affiliations:MPI für physiologische und klinische Forschung
Identifiers:ISSN:0006-3002 (Print) 0006-3002 (Linking) %R 10.1016/j.bbadis.2013.04.006
URL:http://www.ncbi.nlm.nih.gov/pubmed/23579073
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