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- Title
Sex-dependent compensatory mechanisms preserve blood pressure homeostasis in prostacyclin receptor-deficient mice.
- Authors
Tang, Soon Y.; Hu Meng; Anderson, Seán T.; Sarantopoulou, Dimitra; Ghosh, Soumita; Lahens, Nicholas F.; Theken, Katherine N.; Ricciotti, Emanuela; Hennessy, Elizabeth J.; Tu, Vincent; Bittinger, Kyle; Weiljie, Aalim M.; Grant, Gregory R.; FitzGerald, Garret A.; Meng, Hu; Weljie, Aalim M
- 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 deficiency in PGI2 to maintain BP homeostasis in response to high salt in hyperlipidemic female mice. In male mice, by contrast, the augmented formation of atrial natriuretic peptide (ANP) plays a similar compensatory role, restraining hypertension and oxidant stress in the setting of Ipr depletion. Hence, men with hyperlipidemia on a HSD might be at risk of a hypertensive response to mPGES-1 inhibitors.
- Subjects
HOMEOSTASIS; BLOOD pressure; CYCLOOXYGENASES; PROSTACYCLIN; HIGH-salt diet; HUMAN reproduction; CELL receptors; MICE; ANIMALS
- Publication
Journal of Clinical Investigation, 2021, Vol 131, Issue 14, p1
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI136310