Hyperhomocysteinemia is detrimental to pregnancy in mice and is associated with preterm birth

S. R. Sonne, V. K. Bhalla, Scott A Barman, R. E. White, S. Zhu, T. M. Newman, Puttur D Prasad, Sylvia B Smith, S. Offermanns, V. Ganapathy

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

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 β-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.

Original languageEnglish (US)
Pages (from-to)1149-1158
Number of pages10
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1832
Issue number8
DOIs
StatePublished - May 14 2013

Fingerprint

Hyperhomocysteinemia
Premature Birth
Homocysteine
Pregnancy
Dinoprostone
Uterus
Cystathionine
Oxytocin Receptors
Cell Line
Uterine Contraction
Niacin
Trophoblasts
Patch-Clamp Techniques
Human Activities
Placenta
Up-Regulation
Pharmacology
Gene Expression

Keywords

  • Cyclooxygenase-2
  • Homocysteine
  • Niacin receptor
  • Preterm birth
  • Prostaglandin E2

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology

Cite this

Hyperhomocysteinemia is detrimental to pregnancy in mice and is associated with preterm birth. / Sonne, S. R.; Bhalla, V. K.; Barman, Scott A; White, R. E.; Zhu, S.; Newman, T. M.; Prasad, Puttur D; Smith, Sylvia B; Offermanns, S.; Ganapathy, V.

In: Biochimica et Biophysica Acta - Molecular Basis of Disease, Vol. 1832, No. 8, 14.05.2013, p. 1149-1158.

Research output: Contribution to journalArticle

Sonne, S. R. ; Bhalla, V. K. ; Barman, Scott A ; White, R. E. ; Zhu, S. ; Newman, T. M. ; Prasad, Puttur D ; Smith, Sylvia B ; Offermanns, S. ; Ganapathy, V. / Hyperhomocysteinemia is detrimental to pregnancy in mice and is associated with preterm birth. In: Biochimica et Biophysica Acta - Molecular Basis of Disease. 2013 ; Vol. 1832, No. 8. pp. 1149-1158.
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