Microsomal Prostaglandin Synthase-1–Derived Prostaglandin E
            <sub>2</sub>
            Protects Against Angiotensin II–Induced Hypertension via Inhibition of Oxidative Stress

Jia, Zhanjun; Guo, Xiang-Zhao; Zhang, Hui; Wang, Mong Heng; Dong, Zheng; Yang, Tianxin

doi:10.1161/hypertensionaha.108.111229

Cited by 54 publications

(47 citation statements)

References 38 publications

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“…In our present study, we speculated that the effect of renal mPGES-1 may not be apparent during the short term AngII infusion since there was no significant difference in urine output and sodium excretion between wild-type and mPGES-1 -/-mice during the 30-min AngII infusion. However, we cannot exclude the important effect of renal mPGES-1 in hypertenison because in previous reports [29,30] , the antihypertensive effect of renal mPGES-1-derived PGE2 appears to be critical in chronic settings, including long-term AngII infusion and high salt diet.To further characterize the underlying mechanism involved in the hypotensive effect of mPGES-1-derived PGE2 during acute infusion of AngII, we measured PGE2 release from isolated mesenteric arteries and found that acute AngII treatment resulted in a significant increase in PGE2 release in wild-type mice but not mPGES-1 -/-mice. Based on the fact that acute infusion of angiotensin II did not yield a significant mPGES-1 protein induction, we speculated that angiotensin II may stimulate the release of PGE2 through preexisting mPGES-1 protein in the vessels.…”

mentioning

confidence: 83%

Enhanced pressor response to acute Ang II infusion in mice lacking membrane-associated prostaglandin E2 synthase-1

Zhang

Yang

et al. 2010

Acta Pharmacol Sin

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Aim: To examine the contribution of vascular membrane-associated prostaglandin E2 synthase-1 (mPGES-1) to acute blood pressure homeostasis. Methods: Angiotensin II (AngII, 75 pmol·kg -1 ·min -1 ) was continuously infused via the jugular vein into wild-type and mPGES-1 -/-mice for 30 min, and blood pressure was measured by carotid arterial catheterization. RT-PCR and immunohistochemistry were performed to detect the expression and localization of mPGES-1 in the mouse arterial vessels. Mesenteric arteries were dissected from mice of both genotypes to study vessel tension and measure vascular PGE2 levels. Results: Wild-type and mPGES-1 -/-mice showed similar blood pressure levels at baseline, and the acute intravenous infusion of AngII caused a greater increase in mean arterial pressure in the mPGES-1 -/-group, with a similar diuretic and natriuretic response in both groups. mPGES-1 was constitutively expressed in the aortic and mesenteric arteries and vascular smooth muscle cells of wild-type mice. Strong staining was detected in the smooth muscle layer of arterial vessels. Ex vivo treatment of mesenteric arteries with AngII produced more vasodilatory PGE2 in wild-type than in mPGES-1 -/-mice. In vitro tension assays further revealed that the mesenteric arteries of mPGES-1 -/-mice exhibited a greater vasopressor response to AngII than those arteries of wild-type mice. Conclusion: Vascular mPGES-1 acts as an important tonic vasodilator, contributing to acute blood pressure regulation.Keywords: prostaglandin E2; membrane-associated prostaglandin E2 synthase-1; angiotensin II; blood pressure; resistant vessel Acta Pharmacologica Sinica (2010Sinica ( ) 31: 1284Sinica ( -1292 doi: 10.1038/aps.2010 published online 27 Sep 2010 Original Article * To whom correspondence should be addressed. [14] , but its relative contribution to PGE2 generation in vivo remains largely uncharacterized. The third form of PGES (cPGES) was originally isolated from cytoplasmic extracts and is expressed ubiquitously in a constitutive housekeeping manner and functionally coupled with COX-1 to generate physiological PGE2 [15,16] . A large body of evidence demonstrates that PGE2 exerts both vasoconstrictive and vasodilatory actions via its four G-protein coupled receptors: EP1, EP2, EP3, and EP4 [17,18] . However, the net effect of PGE2 appears to be the reduction of blood pressure [19][20][21] . This finding is consistent with clinical observations that nonsteroidal anti-inflammatory drugs (NSAIDs), such as COX inhibitors, can cause hypertension [22][23][24] . Similarly, COX-2 inhibitors increase blood pressure in both animals and patients [25][26][27][28] , which suggests that COX-2-derived prostaglandins are predominantly the vasodilators. Since mPGES-1 is generally believed to be coupled with COX-2 to mediate PGE2 biosynthesis, mPGES-1-derived PGE2 may also exert a vasodepressor effect in vivo. Indeed, recent studies found that deletion of the mPGES-1 gene caused a hypersensitive phenotype in response to chronic salt loading and angiotens...

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confidence: 83%

Enhanced pressor response to acute Ang II infusion in mice lacking membrane-associated prostaglandin E2 synthase-1

Zhang

Yang

et al. 2010

Acta Pharmacol Sin

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“…Increased sympathetic activity has been related to increased oxidative stress in models of renovascular hypertension (22) and in brains of animals with salt-sensitive hypertension (5) but whether this occurs in mPGES-1 KO mice requires further study. Jia et al (14) recently reported that mPGES-1 KO mice exhibit increased renal vascular resistance after an acute infusion of ANG II that correlated with increased mean arterial pressure in these animals. The authors suggested that the absence of mPGES-1 exposes the mice to greater oxidative stress in the vasculature after ANG II infusion and that it is the antioxidant properties of PGE 2 that are responsible for its protective effect.…”

Section: ·Daymentioning

confidence: 96%

Lack of microsomal prostaglandin E synthase-1 reduces cardiac function following angiotensin II infusion

Harding

Yang

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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Harding P, Yang XP, He Q, LaPointe MC. Lack of microsomal prostaglandin E synthase-1 reduces cardiac function following angiotensin II infusion. Am J Physiol Heart Circ Physiol 300: H1053-H1061, 2011. First published December 30, 2010 doi:10.1152/ajpheart.00772.2010.-Our laboratory previously reported that inducible PGE2 synthase, mPGES-1, contributes to micromolar production of PGE2 in neonatal ventricular myocytes in vitro, which stimulates their growth. We therefore hypothesized that mPGES-1 contributes to cardiac hypertrophy following angiotensin II (ANG II) infusion. To test this hypothesis, we used 10-to 12-wk-old mPGES-1 knockout mice (mPGES-1 KO) and C57Bl/6 control mice infused for 8 wk with either 1.4 mg·kg Ϫ1 ·day Ϫ1ANG II or vehicle subcutaneously. Blood pressure [systolic blood pressure (SBP)] was measured throughout the study, and cardiac function was assessed by M-mode echocardiography at baseline and at 8 wk of infusion. At the conclusion of the study, immunohistochemistry was used to evaluate collagen fraction, myocyte crosssectional area (MCSA), and apoptosis. At baseline, there was no difference in SBP between mPGES-1 KO mice and C57BL/6 controls. ANG II infusion increased SBP to similar levels in both strains. In control mice, infusion of ANG II increased MCSA and posterior wall thickness at diastole (PWTd) but had little effect on cardiac function, consistent with compensatory hypertrophy. In contrast, cardiac function was worse in mPGES-1 KO mice after ANG II treatment. Ejection fraction declined from 76.2 Ϯ 2.7 to 63.3 Ϯ 3.4% after ANG II, and left ventricular dimension at systole and diastole increased from 1.29 Ϯ 0.02 to 1.78 Ϯ 0.15 mm and from 2.57 Ϯ 0.03 to 2.90 Ϯ 0.13 mm, respectively. Infusion of ANG II increased both the LV-to-body weight and the mass-to-body weight ratios to a similar extent in both strains. However, PWTd increased by a lesser extent in KO mice, suggesting an impaired hypertrophic response. ANG II infusion increased collagen staining similarly in both strains, but TdT-dUTP nick end labeling staining was greater in mPGES-1 KO mice. Overall, these results are consistent with a beneficial effect for mPGES-1 in the maintenance of cardiac function in ANG II-dependent hypertension.microsomal prostaglandin E synthase-1; angiotensin II; hypertrophy THE ENZYME PROSTAGLANDIN E synthase exists in three isoforms, a cytosolic form (cPGES) and two microsomal forms (mPGES-1 and mPGES-2), that are membrane attached. In contrast to mPGES-1, mPGES-2 is not activated by proinflammatory factors and is believed to play a constitutive role in PGE 2 formation. Our laboratory has previously demonstrated the existence of mPGES-1 in cardiac myocytes and fibroblasts after stimulation with interleukin-1␤, and this appears to be colocalized with cyclooxygenase (COX)-2 in a perinuclear manner (6).A number of studies demonstrate the induction of mPGES-1 coupled with increased PGE 2 production in rodent models of myocardial infarction (MI). A report from our laboratory (18) indicated that treatm...

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“…Inhibition of COX-2 leads to an imbalance of prothrombotic prostaglandins (increased TxA 2 ) and antithrombotic prostaglandins (decreased PGI 2 ) that is proposed to increase the risk of MI and stroke 33 and to increase mortality after MI. 34 Deletion of mPGES-1, downstream from COX-2 in the inducible PGE 2 biosynthetic cascade, decreases brain ischemia-reperfusion injury, 35 plaque burden in fat-fed Ptges -/-low-density lipoprotein receptor-deficient (LDLR -/-) mice, 36 aortic aneurysm formation, 37 and DOCA-salt-and angiotensin II-induced hypertension, 38 as well as pain, fever, and inflammation in animal models of these diseases. 13,39 Conversely, global deletion of mPGES-1 does not disturb the balance between prothrombotic and antithrombotic prostaglandin production in vivo.…”

Section: Degousee Et Almentioning

confidence: 99%

Lack of Microsomal Prostaglandin E ₂ Synthase-1 in Bone Marrow–Derived Myeloid Cells Impairs Left Ventricular Function and Increases Mortality After Acute Myocardial Infarction

et al. 2012

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Background-Microsomal prostaglandin E 2 synthase-1 (mPGES-1), encoded by the Ptges gene, catalyzes prostaglandin E 2 biosynthesis and is expressed by leukocytes, cardiac myocytes, and cardiac fibroblasts. Ptges Ϫ/Ϫ mice develop more left ventricle (LV) dilation, worse LV contractile function, and higher LV end-diastolic pressure than Ptges ϩ/ϩ mice after myocardial infarction. In this study, we define the role of mPGES-1 in bone marrow-derived leukocytes in the recovery of LV function after coronary ligation. Methods and Results-Cardiac structure and function in Ptgesϩ/ϩ mice with Ptges ϩ/ϩ bone marrow (BM ϩ/ϩ ) and Ptges ϩ/ϩ mice with Ptges Ϫ/Ϫ BM (BM Ϫ/Ϫ ) were assessed by morphometric analysis, echocardiography, and invasive hemodynamics before and 7 and 28 days after myocardial infarction. Prostaglandin levels and prostaglandin biosynthetic enzyme gene expression were measured by liquid chromatography-tandem mass spectrometry and real-time polymerase chain reaction, immunoblotting, immunohistochemistry, and immunofluorescence microscopy, respectively. After myocardial infarction, BM Ϫ/Ϫ mice had more LV dilation, worse LV systolic and diastolic function, higher LV end-diastolic pressure, more cardiomyocyte hypertrophy, and higher mortality but similar infarct size and pulmonary edema compared with BM ϩ/ϩ mice. BM Ϫ/Ϫ mice also had higher levels of COX-1 protein and more leukocytes in the infarct, but not the viable LV, than BM ϩ/ϩ mice. Levels of prostaglandin E 2 were higher in the infarct and viable myocardium of BM Ϫ/Ϫ mice than in BM ϩ/ϩ mice. Conclusions-Lack of mPGES-1 in bone marrow-derived leukocytes negatively regulates COX-1 expression, prostaglandin E 2 biosynthesis, and inflammation in the infarct and leads to impaired LV function, adverse LV remodeling, and decreased survival after acute myocardial infarction. (Circulation. 2012;125:2904-2913.)Key Words: leukocytes Ⅲ myocardial infarction Ⅲ prostaglandins Ⅲ remodeling Ⅲ chimeric mice I schemic heart disease and myocardial infarction (MI) will be the leading cause of death worldwide by 2020. 1 MI leads to an inflammatory response characterized by the generation of proinflammatory mediators and the influx of leukocytes that are necessary to remove necrotic cellular debris and promote recovery of left ventricular (LV) contractile function. An improperly regulated inflammatory response and pathological LV remodeling can impair LV function and lead to heart failure and death after MI. 2,3 Editorial see p 2818 Clinical Perspective on p 2913Prostaglandins, synthesized by the sequential action of phospholipase A 2 (PLA 2 ), cyclooxygenases (COX-1 and/or Received November 28, 2011; accepted April 4, 2012. 12 Collectively, these observations suggest a beneficial role for mPGES-1-mediated PGE 2 biosynthesis in postinfarction LV remodeling. The cellular source of mPGES-1 in the heart after MI has not been identified. In this study, we show that deletion of mPGES-1 in bone marrow-derived leukocytes results in a more intense inflammatory response, patholog...

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Microsomal Prostaglandin Synthase-1–Derived Prostaglandin E ₂ Protects Against Angiotensin II–Induced Hypertension via Inhibition of Oxidative Stress

Cited by 54 publications

References 38 publications

Enhanced pressor response to acute Ang II infusion in mice lacking membrane-associated prostaglandin E2 synthase-1

Enhanced pressor response to acute Ang II infusion in mice lacking membrane-associated prostaglandin E2 synthase-1

Lack of microsomal prostaglandin E synthase-1 reduces cardiac function following angiotensin II infusion

Lack of Microsomal Prostaglandin E ₂ Synthase-1 in Bone Marrow–Derived Myeloid Cells Impairs Left Ventricular Function and Increases Mortality After Acute Myocardial Infarction

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Microsomal Prostaglandin Synthase-1–Derived Prostaglandin E 2 Protects Against Angiotensin II–Induced Hypertension via Inhibition of Oxidative Stress

Cited by 54 publications

References 38 publications

Enhanced pressor response to acute Ang II infusion in mice lacking membrane-associated prostaglandin E2 synthase-1

Enhanced pressor response to acute Ang II infusion in mice lacking membrane-associated prostaglandin E2 synthase-1

Lack of microsomal prostaglandin E synthase-1 reduces cardiac function following angiotensin II infusion

Lack of Microsomal Prostaglandin E 2 Synthase-1 in Bone Marrow–Derived Myeloid Cells Impairs Left Ventricular Function and Increases Mortality After Acute Myocardial Infarction

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Microsomal Prostaglandin Synthase-1–Derived Prostaglandin E ₂ Protects Against Angiotensin II–Induced Hypertension via Inhibition of Oxidative Stress

Lack of Microsomal Prostaglandin E ₂ Synthase-1 in Bone Marrow–Derived Myeloid Cells Impairs Left Ventricular Function and Increases Mortality After Acute Myocardial Infarction