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Role of Microsomal Prostaglandin E Synthase-1 (Mpges1)-Derived PGE2 in Patency of the Ductus Arteriosus in the Mouse

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Role of Microsomal Prostaglandin E Synthase-1 (Mpges1)-Derived PGE2 in Patency of the Ductus Arteriosus in the Mouse 0031-3998/08/6405-0523 Vol. 64, No. 5, 2008 PEDIATRIC RESEARCH Printed in U.S.A. Copyright © 2008 International Pediatric Research Foundation, Inc. Role of Microsomal Prostaglandin E Synthase-1 (mPGES1)-Derived PGE2 in Patency of the Ductus Arteriosus in the Mouse BARBARA BARAGATTI, DARIA SODINI, SATOSHI UEMATSU, AND FLAVIO COCEANI Scuola Superiore Sant’Anna and Institute of Clinical Physiology CNR [B.B., D.S., F.C.], Pisa 56100, Italy; Department of Host Defence [S.U.], Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan ABSTRACT: Prostaglandin E2 (PGE2) plays a key role in the ductus close or even equal in magnitude to that of a dual COX1/ arteriosus, prenatally by maintaining patency and postnatally by COX2 inhibitor (7–9); the greater impairment of PGE2-based promoting tissue remodeling for closure. Here, by using near-term relaxation upon COX2 than COX1 deletion (5) along with the mouse fetuses with (wild-type, WT) and without microsomal PGE marked curtailment of PGE formation after inhibition of Ϫ Ϫ 2 synthase-1 (mPGES1 / ), we have examined the importance of this either COX2 or mPGES1 (6,7). Consistent with the preferen- enzyme for PGE formation and function. mPGES1Ϫ/Ϫ ductus, 2 tial operation of the COX2/mPGES1 route for PGE synthesis unlike WT ductus, contracted little, or not all, to indomethacin in 2 G is also evidence from adult blood vessels (10) and the notion that vitro. Coincidentally, as evident from responses to N -nitro-L- arginine methyl ester and zinc photoporphyrin, the mutant showed no mPGES1 is catalytically most active among the PGES (11). significant enhancement of nitric oxide (NO)- and carbon monoxide Despite these facts, previous attempts to prove the actual (CO)-based relaxation. mPGES1 suppression differs, therefore, from importance of the COX2/mPGES1 pathway for ductus pa- cyclooxygenase (COX) suppression, whether genetically or pharma- tency have failed. As shown by others and ourselves (5,12,13), cologically induced, where NO is markedly up-regulated. In vivo, the COX2 removal does not result in loss of patency, likely thanks ductus was patent, albeit occasionally with a narrowed lumen, in all to compensation from COX1-derived PGE2 and nonPG agents mPGES1Ϫ/Ϫ fetuses. Conversely, postnatal closure progressed reg- such as nitric oxide (NO) and carbon monoxide (CO). Indeed, Ϫ Ϫ ularly in mPGES1 / animals thanks to residual PGE2 originating COX2 removal, even if limited to a single allele, is followed via mPGES2. We conclude that mPGES1 is critical for PGE for- 2 by selective up-regulation of NO (5,14). An additional com- mation in the ductus but its loss does not entail compensatory up- plication in addressing this issue is that PGE not only sustains regulation of other relaxing mechanisms. Accordingly, an mPGES1 2 inhibitor stands out as a prospective better tool, compared with the patency of the ductus in utero, but also promotes its closure currently used COX inhibitors, for the management of premature infants after birth (9,15,16). Hence, COX2/mPGES1 function needs with persistent ductus. (Pediatr Res 64: 523–527, 2008) to be considered pre and postnatally. Our objective here was 2-fold: first, to assess the impor- tance of mPGES1 in ensuring normal patency and closure of rostaglandin (PG) E2 is viewed as the prime agent for Pprenatal patency of the ductus arteriosus (1). Conversely, the ductus, and second, to ascertain whether mPGES1 removal mimics COX2 removal in up-regulating NO. CO was exam- PGI2 is without a role, notwithstanding its occurrence in the vessel and its known importance for vasoregulation elsewhere ined comparatively to verify the specificity of any such effect. An answer to these questions is important insofar as it may (2,3). Ductal PGE2 is formed primarily through the cycloox- ygenase-2 (COX2)/microsomal PGE synthase-1 (mPGES1) provide a better insight into the functional organization of the complex, while little of the compound originates from the PGE2 system and the role of PGE2 vis-a`-vis NO and CO in COX1/mPGES1 complex and none at all from cytosolic ductus relaxation. In addition, any advance in this area may PGES (cPGES). No information is available on microsomal lead to better agents, in comparison to the currently used COX PGE synthase-2 (mPGES2), but evidence from other vascular inhibitors (17), for the management of the prematurely born districts points to its minor function (4). Several findings infant with patent ductus (PDA). support this arrangement in the ductus, namely, immunocyto- chemical data showing a predominant colocalization of COX2 METHODS with mPGES1 (5); the increase in COX2 and mPGES1 ex- ϫ pression occurring selectively through development (6); the Animals. Experiments were carried out in 129 C57BL/6 mice with mPGES1Ϫ/Ϫ genotype (18) (litter size, 2–9; mean, 4), and wild-type (WT) constrictor action of COX2 inhibitors on the ductus, being C57BL/6 mice (litter size, 1–12; mean, 5) served as a control. In either case, genotype was confirmed in tail specimens by polymerase chain reaction (PCR). Animals were housed in temperature- and humidity-controlled quar- Received February 21, 2008; accepted June 20, 2008. Correspondence: Flavio Coceani, M.D., Scuola Superiore Sant’Anna, Piazza Martiri della Liberta` 33, Pisa 56127, Italy; email: [email protected] G Abbreviations: COX, cyclooxygenase; L-NAME, N -nitro-L-arginine methyl Supported by grants of the Italian Ministry of Education and Research (FIRB ester; mPGES1, microsomal PGE synthase-1; mPGES2, microsomal PGE syn- RBNEOIW9 PM; PRIN 2005053227). D.S. was the recipient of a graduate studentship from the Scuola Superiore Sant’Anna. thase-2; ONO-11113, 9, 11-epithio-11, 12-methano-thromboxane A2; PDA, B.B. and D.S. contributed equally to this study. patent ductus arteriosus; PG, prostaglandin; ZnPP, zinc protoporphyrin 523 524 BARAGATTI ET AL. ters with constant 12:12-h light-dark cycles and were given food and water ad 1% methylene blue. Care was taken to collect a complete series of ductus libitum. Surgical procedures and experimental protocols were approved by the sections. Afterward, each section was photographed with a charge-coupled Animal Care Committee of the Ministry of Health. device solid-state camera (COHU, San Diego, CA) and lumen area of the In vitro studies. Term fetal mice, both WT and gene-deleted (gestational ductus was measured with a MCID-M4 program (Brock University, St. age, 19 d), were delivered by cesarean section under halothane anesthesia and Catharines, Canada). Both maximal and minimal values of this area were were killed by cervical dislocation. Body weight varied between 0.9 and 1.4 g, retrieved from each series for computation. and only one fetus was used in each experiment. The procedure for dissection Total RNA preparation and quantitative RT-PCR. mPGES2 expression of the ductus arteriosus, normalization of internal circumference and mechan- was measured to assess any change resulting from mPGES1 deletion. For this ical record has been described previously (19). In brief, the animal was purpose, ductuses were collected from WT and mPGES1 null fetuses and secured with its left side up in a dissection chamber containing ice-cold Krebs were pooled in three separate groups for each genotype (35–41 specimens/ solution gassed with 5% CO2 in N2. Through a thoracotomy, the ductus was group). RNA was then isolated as described earlier (5), and its yield was exposed, separated from the adjoining large blood vessels and then suspended measured spectrophotometrically. DNAse I (Roche, Indianapolis, IN)— onto 25-␮m tungsten wires (Cooner wire, Chatsworth, CA) inside an organ treated total RNA (2.5 ␮g) was reverse transcribed with1UofThermoscript bath. The fluid of the bath was gassed with a mixture containing 2.5% O2 to RT (Invitrogen, Carlsbad, CA) in the presence of random hexanucleotide mimic the fetal condition, and the same gas mixture was flushed through a primers according to the manufacturer’s instructions. QRT-PCR reactions (40 hood covering the bath. Preparations were then equilibrated (about 60 min at cycles) were performed on an ABI Prism 7700 instrument (Applied Biosys- 37°C) with a minimal stretch being applied (all values in mN mmϪ1) (WT, tems, Foster City, CA) using the TaqMan Universal PCR Master Mix (Applied 0.09 Ϯ 0.01 (n ϭ 14); mPGES1Ϫ/Ϫ, 0.08 Ϯ 0.008 (n ϭ 16)) and the Biosystems). Primer sequences for mPGES2 and cyclophilin B (internal attendant internal circumference (C0) with the related resting dimension standard) were obtained from an online library (Applied Biosystems). Gene (Table 1) served as a reference for choosing the appropriate load. Afterward, expression was quantified in triplicate for each group, using the comparative tension was applied to attain an operating circumference (i.e. C50) coinciding cycle-threshold method and cyclophilin for normalization. with the condition in vivo (WT, 0.45 Ϯ 0.007 (n ϭ 14); mPGES1Ϫ/Ϫ, 0.45 Ϯ Solutions and drugs. The Krebs medium had the following composition ϭ Ϫ1 0.009 (n 16); values in mN mm ), and the actual experiment was started (mM): NaCl 118, KCl 4.7, CaCl2 2.5, KH2PO4 1, MgSO4 0.9, dextrose 11.1, after a second, 60- to 150-min period of equilibration. and NaHCO3 25. Depending on the stage of the experiment (see above), the The study consisted of a single protocol with two test procedures, address- solution was bubbled with gas mixtures containing either no O2 or 2.5% O2 G ing respectively the effect of N -nitro-L-arginine methyl ester (L-NAME, 100 plus 5% CO2 and balance N2.PO2 was measured with a Chiron gas analyzer ␮M; n ϭ 13) and zinc protoporphyrin (ZnPP, 10 ␮M; n ϭ 8) on the basal (mod. 248, Halstead, UK) and was 0.95 Ϯ 0.0009 and 2.14 Ϯ 0.02 kPa (pH, ␮ ϭ Ϯ tone.
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