Gene deletion studies reveal a critical role for prostamide/prostaglandin F2αsynthase in prostamide F2αformation

Abstract

AbstractProstamide/prostaglandin F synthase (PM/PGFS) is an enzyme with very narrow substrate specificity and is dedicated to the biosynthesis of prostamide and prostaglandin F2α.The importance of this enzyme, relative to the aldoketoreductase (AKR) series, in providing functional tissue prostamide F2αlevels was determined by creating a line of PM/PGFS gene deleted mice. Deletion of the gene encoding PM/PGFS (fam213b) was accomplished by a two exon disruption. Prostamide F2αlevels in WT and PM/PGFS KO mice were determined by LC/MS/MS. Intraocular pressure was measured by tonometry and outflow facility was measured by theiPerfusionmethod in enucleated mouse eyes. Deletion of fam213b had no observed effect on behavior, appetite, or fertility. Intraocular pressure was significantly elevated by approximately 4 mmHg in PM/PGFS KO mice compared to littermate WT mice. No effect on pressure dependent outflow facility occurred, which is consistent with the typically reported prostanoid effect of increasing outflow through the unconventional pathway. The elevation of intraocular pressure caused by deletion of the gene encoding the PM/PGFS enzyme likely results from a diversion of the endoperoxide precursor pathway to provide increased levels of those prostanoids that raise intraocular pressure, namely prostaglandin D2(PGD2), thromboxane A2(TxA2). It follows that PM/PGFS may serve an important regulatory role in the eye by providing PGF2αand prostamide F2αto constrain the influence of those prostanoids that raise intraocular pressure.