Prostacyclin protects against elevated blood pressure and cardiac fibrosis

François, H.; Athirakul, Krairerk; Howell, David N.; Dash, Rajesh; Mao, Lan; Kim, Hyung Suk; Rockman, Howard A.; FitzGerald, Garret A.; Koller, Beverly H.; Coffman, Thomas M.

doi:10.1016/j.cmet.2005.08.005

Cited by 141 publications

(122 citation statements)

References 40 publications

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“…This finding is consistent with the recent report by Cheng et al (38), who also found no difference in BP between mPges1 Ϫ/Ϫ and WT control mice on either normal-or high-salt diet. Furthermore, our previous studies implicated alterations in PGI 2 in NSAID-associated hypertension (48). Nonetheless, it is still possible that mPGES1 might have played a role in modulating BP and vascular tone on a different genetic background or in models of hypertension.…”

Section: Discussionmentioning

confidence: 99%

Role of Microsomal Prostaglandin E Synthase 1 in the Kidney

François

Facemire

Kumar

et al. 2007

Journal of the American Society of Nephrology

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Prostaglandin E 2 (PGE 2 ) is one of the most ubiquitous prostanoids in the kidney, where it may influence a wide range of physiologic functions. PGE 2 is generated through enzymatic metabolism of prostanoid endoperoxides by specific PGE synthases (PGES). Several putative PGES have been identified and cloned, including the membrane-associated, inducible microsomal PGES1 (mPGES1), which is expressed in the kidney. To evaluate the physiologic role of mPGES1 in the kidney, mice with targeted disruption of mPges1 gene were studied, with a focus on responses where PGE 2 has been implicated, including urinary concentration, regulation of blood pressure, and response to a loop diuretic. The absence of mPGES1 was associated with a 50% decrease in basal excretion of PGE 2 in urine (P < 0.001). In female but not male mPGES1-deficient mice, there was a reciprocal increase in basal excretion of other prostanoids. Nonetheless, urinary osmolalities were similar in mPges1 ؉/؉ and mPges1 ؊/؊ mice at baseline and after 12 h of water deprivation. Likewise, there were no differences in blood pressure between mPGES1-deficient and wild-type mice on control or high-or low-salt diets. The furosemide-induced increase in urinary PGE 2 excretion that was seen in wild-type mice was attenuated in mPGES1-deficient mice. However, furosemide-associated diuresis was reduced only in male, not female, mPGES1-deficient mice. Stimulation of renin by furosemide was not affected by mPGES1 deficiency. These data suggest that mPGES1 contributes to basal synthesis of PGE 2 , but there are other pathways that lead to renal PGE 2 synthesis. Moreover, there are significant gender differences in physiologic contributions of mPGES1 to control kidney function.

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Section: Discussionmentioning

confidence: 99%

Role of Microsomal Prostaglandin E Synthase 1 in the Kidney

François

Facemire

Kumar

et al. 2007

Journal of the American Society of Nephrology

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“…Blood pressure was unaltered in PGHS-1 KD mice, but the hypertensive effect of celecoxib was attenuated in these mice ( Figure 3C). Thus, selective disruption or deletion of PGHS-2, just like deletion of the IP (22), can result in an elevation of blood pressure in mice, and this effect is attenuated by genetic mimicking of the impact of low-dose aspirin. This contrasts with the impact of TP deletion on the hypertensive response to IP deletion.…”

Section: Impact Of Pghs Inhibition Knock Down Mutation or Knockoutmentioning

confidence: 99%

Cyclooxygenases, microsomal prostaglandin E synthase-1, and cardiovascular function

Cheng

Wang²,

Yu³

et al. 2006

Journal of Clinical Investigation

319

282

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We investigated the mechanisms by which inhibitors of prostaglandin G/H synthase-2 (PGHS-2; known colloquially as COX-2) increase the incidence of myocardial infarction and stroke. These inhibitors are believed to exert both their beneficial and their adverse effects by suppression of PGHS-2-derived prostacyclin (PGI 2 ) and PGE 2 . Therefore, the challenge remains to identify a mechanism whereby PGI 2 and PGE 2 expression can be suppressed while avoiding adverse cardiovascular events. Here, selective inhibition, knockout, or mutation of PGHS-2, or deletion of the receptor for PGHS-2-derived PGI 2 , was shown to accelerate thrombogenesis and elevate blood pressure in mice. These responses were attenuated by COX-1 knock down, which mimics the beneficial effects of low-dose aspirin. PGE 2 biosynthesis is catalyzed by the coordinate actions of COX enzymes and microsomal PGE synthase-1 (mPGES-1). We show that deletion of mPGES-1 depressed PGE 2 expression, augmented PGI 2 expression, and had no effect on thromboxane biosynthesis in vivo. Most importantly, mPGES-1 deletion affected neither thrombogenesis nor blood pressure. These results suggest that inhibitors of mPGES-1 may retain their antiinflammatory efficacy by depressing PGE 2 , while avoiding the adverse cardiovascular consequences associated with PGHS-2-mediated PGI 2 suppression.

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“…The basic literature is replete with recent studies demonstrating that genomic or pharmacological removal of prostacyclin leads to both platelet-dependent [13][14][15] and plateletindependent 16 mechanisms for induction of thrombosis, plaque destabilization, or atherogenesis. In addition, COX-2 is recognized as a key source of prostacyclin under normal laminar flow conditions in the vasculature and has been shown to be cardioprotective in ischemia-reperfusion injury.…”

Section: Pharmacology Of Cox Inhibitionmentioning

confidence: 99%

Cardiovascular Effects of the Cyclooxygenase Inhibitors

White

2007

Hypertension

106

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C yclooxyenase (COX)-2 selective inhibitors were developed to create a new class of nonsteroidal antiinflammatory drugs (NSAIDs) with properties similar to those of nonselective NSAIDS but without their potential COX-1-mediated gastrointestinal toxicities. 1,2 Studies of the various COX-2 selective inhibitors have shown that they are in fact associated with a significantly lower risk of upper and lower gastrointestinal complications than traditional NSAIDs, except in patients who are taking concomitant low-doses of aspirin.Recent evidence also suggests that some doses of the COX-2 selective inhibitors, and perhaps some traditional NSAIDs as well, are associated with an increased risk of adverse cardiovascular (CV) events. Reports of a higher incidence of myocardial infarction (MI) among patients with arthritis taking high doses of the COX-2 selective inhibitor rofecoxib compared with those taking the NSAID naproxen 2-4 have had heightened concerns since 2001 regarding selective COX-2 inhibitor safety. In addition, in early 2005, elevated CV event rates were reported in patients with spontaneous adenomatous polyps who were taking high doses of celecoxib compared with placebo 5 and in patients who received parenteral parecoxib followed by oral valdecoxib versus placebo immediately after coronary artery bypass graft surgery. 6 This article represents a compilation of the data concerning the effects of both nonselective and selective NSAIDs on blood pressure (BP), particularly in patients with hypertension and/or on antihypertensive agents. Subsequently, the impact that the COX inhibitors have on CV events from several recent clinical trials for the treatment of arthritis or for cancer prevention, as well as from selected large observational studies, is discussed. CV Pharmacology of COX InhibitionCOXs participate in numerous physiological functions and human pathological disorders. The COX-1 isoform is constitutively expressed in most tissues where it regulates the synthesis of prostaglandins. COX-1 is the only form of the enzyme in mature platelets and is also expressed in the vascular endothelium, the gastrointestinal epithelium, brain, spinal cord, and kidney. The COX-2 isoform plays an important role in induction of inflammation in response to injury, as well as later repair of inflammation. It is noteworthy that COX-2 may be induced by bacterial endotoxins, cytokines, and growth factors and is expressed in atherosclerotic plaques, during angiogenesis, during wound healing, and in a variety of epithelial cell cancers. [7][8][9] In addition, COX-2 is constitutively expressed in the macula densa and renal medullary interstitium. 10,11 As discussed below, one result of COX-2 inhibition is a reduction in natriuresis and the development of hypertension in susceptible populations. The COX isoenzymes are similar in structure, but the substrate-binding channel of COX-2 contains a side pocket that is absent in COX-1. This structural difference has allowed for the design and development of COX inhibitors with side chains ...

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Prostacyclin protects against elevated blood pressure and cardiac fibrosis

Cited by 141 publications

References 40 publications

Role of Microsomal Prostaglandin E Synthase 1 in the Kidney

Role of Microsomal Prostaglandin E Synthase 1 in the Kidney

Cyclooxygenases, microsomal prostaglandin E synthase-1, and cardiovascular function

Cardiovascular Effects of the Cyclooxygenase Inhibitors

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