Sex-dependent compensatory mechanisms preserve blood pressure homeostasis in prostacyclin receptor-deficient mice.

The Journal of Clinical Investigation
Soon Yew TangGarret A FitzGerald

Abstract

Inhibitors of microsomal prostaglandin E synthase 1 (mPGES-1) are in the early phase of clinical development. Deletion of mPges-1 in mice confers analgesia, restrains atherogenesis, and fails to accelerate thrombogenesis, while suppressing prostaglandin E2 (PGE2), but increasing the biosynthesis of prostacyclin (PGI2). In low-density lipoprotein receptor-deficient (Ldlr-/-) mice, this last effect represents the dominant mechanism by which mPges-1 deletion restrains thrombogenesis, while suppression of PGE2 accounts for its antiatherogenic effect. However, the effect of mPges-1 depletion on blood pressure (BP) in this setting remains unknown. Here, we show that mPges-1 depletion significantly increased the BP response to salt loading in male Ldlr-/- mice, whereas, despite the direct vasodilator properties of PGI2, deletion of the I prostanoid receptor (Ipr) suppressed this response. Furthermore, combined deletion of the Ipr abrogated the exaggerated BP response in male mPges-1-/- mice. Interestingly, these unexpected BP phenotypes were not observed in female mice fed a high-salt diet (HSD). This is attributable to the protective effect of estrogen in Ldlr-/- mice and in Ipr-/- Ldlr-/- mice. Thus, estrogen compensates for a defic...Continue Reading

References

Sep 1, 1975·The Journal of Experimental Medicine·L K DahlR Tuthill
Aug 15, 1994·Annals of Internal Medicine·A G JohnsonR O Day
Oct 10, 1997·Hypertension·J R Haywood, C Hinojosa-Laborde
Dec 22, 1998·Circulation·M P ReillyG A FitzGerald
Feb 13, 2001·The Journal of Clinical Investigation·J L StockL P Audoly
Jun 27, 2002·The American Journal of Cardiology·Michael E Mendelsohn
Mar 15, 2003·Clinical Therapeutics·Edward P Armstrong, Daniel C Malone
Dec 12, 2003·Nature Reviews. Drug Discovery·Garret A FitzGerald
Jan 1, 2004·American Journal of Hypertension·Mohamed A BayorhImad K Abukhalaf
Nov 20, 2004·Science·Karine M EganGarret A Fitzgerald
Jan 7, 2005·Circulation Journal : Official Journal of the Japanese Circulation Society·Hidetsuna WatanabeTsuyoshi Watanabe
Sep 13, 2005·Cell Metabolism·Helene FrancoisThomas M Coffman
Apr 15, 2006·The Journal of Clinical Investigation·Yan ChengGarret A Fitzgerald
Sep 16, 2006·Proceedings of the National Academy of Sciences of the United States of America·Miao WangGarret A FitzGerald
Aug 21, 2007·Clinical Journal of the American Society of Nephrology : CJASN·Raymond C Harris, Matthew D Breyer
Sep 20, 2007·Pharmacological Reviews·Bengt SamuelssonPer-Johan Jakobsson
Dec 30, 2009·Hypertension·Meena S MadhurDavid G Harrison
Jan 26, 2011·Hypertension·Tlili BarhoumiErnesto L Schiffrin
Aug 6, 2011·Canadian Journal of Physiology and Pharmacology·Kailash N Pandey
Dec 6, 2011·Journal of Thrombosis and Haemostasis : JTH·A Smolenski
Aug 1, 2010·Trends in Cardiovascular Medicine·Miao Wang, Garret A FitzGerald
Jul 1, 2015·Biochemical Pharmacology·Andreas Koeberle, Oliver Werz
Dec 18, 2016·American Journal of Physiology. Heart and Circulatory Physiology·Ulrich O WenzelHeimo Ehmke
Mar 11, 2017·Science·Tilo GrosserGarret A FitzGerald
May 30, 2017·Circulation Journal : Official Journal of the Japanese Circulation Society·Tomoko Ichiki, John C Burnett
Jun 28, 2017·Trends in Pharmacological Sciences·Tilo GrosserGarret A FitzGerald
Aug 5, 2017·Science·Luisa Cervantes-BarraganMarco Colonna
Nov 17, 2017·Nature·Nicola WilckDominik N Müller
Feb 6, 2019·Nature Reviews. Immunology·Veit Rothhammer, Francisco J Quintana
Mar 25, 2019·Hypertension·Hendrik BartolomaeusDominik N Muller
Jun 16, 2019·EBioMedicine·Hélène C DescampsChristoph A Thaiss
Jul 22, 2020·Journal of the American Heart Association·Joonatan PalmuTeemu J Niiranen
Feb 3, 2021·The Journal of Clinical Investigation·Allison E NorlanderR Stokes Peebles
Apr 2, 2021·Circulation Research·Meena S MadhurAnnet Kirabo

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Datasets Mentioned

BETA
GSE115916

Methods Mentioned

BETA
RNA-Seq
reverse

Software Mentioned

Ingenuity Pathway Analysis
MetaboAnalyst

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