Overexpression of prostaglandin EP3 receptors activates calcineurin and promotes hypertrophy in the murine heart

Meyer-Kirchrath, Jutta; Martin, Melanie; Schooss, Christina; Jacoby, Christoph; Flögel, Ulrich; Marzoll, Andrea; Fischer, Jens W.; Schrader, Jürgen; Schrör, Karsten; Hohlfeld, Thomas

doi:10.1093/cvr/cvn312

Cited by 30 publications

(29 citation statements)

References 36 publications

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“…Vital and colleagues 11 reported a case of a peripartum heart failure while another case showed that sulprostone caused coronary spasm, bradycardia, and subsequent asystole 12 . In EP3 over-expressing mice, LV ejection fraction was severely decreased in transgenic hearts while the relative LV mass was significantly increased 13 . Using isolated rat atria, Wolkowicz et al 14 also reported that an EP1 agonist increased contractile force that was sensitive to Rho kinase inhibitors.…”

Section: Discussionmentioning

confidence: 95%

Prostaglandin E2 Reduces Cardiac Contractility via EP3 Receptor

Zhu

Bryson

et al. 2016

Circ: Heart Failure

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Background Prostaglandin E2 (PGE2) EP receptors EP3 and EP4 signal via decreased and increased cAMP production, respectively. Previously we reported that cardiomyocyte-specific EP4 KO mice develop dilated cardiomyopathy with reduced ejection fraction. We thus hypothesized that PGE2 increases contractility via EP4 but decreases contractility via EP3. Methods and Results The effects of PGE2 and the EP1/EP3 agonist sulprostone on contractility were examined in the mouse langendorff preparation and in adult mouse cardiomyocytes (AVM). Isolated hearts of adult male C57Bl/6 mice were perfused with PGE2 (10−6M) or sulp (10−6M) and compared to vehicle. Both PGE2 and sulprostone decreased +dp/dt (p<0.01) and left ventricular developed pressure, LVDP, (p<0.001) with reversal by an EP3 antagonist. In contrast, the EP4 agonist had the opposite effect. AVM contractility was also reduced after treatment with either PGE2 or sulprostone for 10 min. We then examined the acute effects of PGE2, sulprostone and the EP4 agonist on expression of phosphorylated phospholamban (PLN) and SERCA2a in AVM using Western blot. Treatment with either PGE2 or sulprostone decreased expression of phosphorylated PLN corrected to total PLN whereas treatment with the EP4 agonist had the opposite effect. SERCA2a expression was unaffected. Finally, we examined the effect of these compounds in vivo using pressure volume loops. Both PGE2 and sulprostone decreased +dp/dt while the EP4 agonist increased +dp/dt. Conclusions Contractility is reduced via the EP3 receptor but increased via EP4. These effects may be mediated through changes in PLN phosphorylation and has relevance to detrimental effects of inflammation.

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Section: Discussionmentioning

confidence: 95%

Prostaglandin E2 Reduces Cardiac Contractility via EP3 Receptor

Zhu

Bryson

et al. 2016

Circ: Heart Failure

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“…Finally, few studies on prostanoid receptor overexpression have been reported. In transgenic mice with cardiospecific EP 3 receptor overexpression, increased calcineurin and NFAT activity with cardiac hypertrophy were found (Meyer-Kirchrath et al, 2009).…”

Section: Distribution and Biological Functionsmentioning

confidence: 99%

International Union of Basic and Clinical Pharmacology. LXXXIII: Classification of Prostanoid Receptors, Updating 15 Years of Progress

Woodward

Jones

Narumiya³

2011

Pharmacol Rev

391

414

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“…Thereby, the cell specific role of EP4 receptor in cardiac remodeling is further required. With regard to EP3, although several reports suggested a cardioprotective effect of EP3 agonists against ischemia/reperfusion injury in rodents and pigs [76–78], others demonstrated that overexpression of EP3 might activate calcineurin and promote hypertrophy after ischemia reperfusion [79]. These results suggest a dual involvement of the EP3 subtype in both cardioprotection and hypertrophy, which might be attributable to the expression diversity of EP3 isoforms in heart tissue.…”

Section: Ep Receptors and Myocardial Remodelingmentioning

confidence: 99%

An Update of Microsomal Prostaglandin E Synthase‐1 and PGE₂ Receptors in Cardiovascular Health and Diseases

Yang

2016

Oxidative Medicine and Cellular Longevity

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Nonsteroidal anti-inflammatory drugs (NSAIDs), especially cyclooxygenase-2 (COX-2) selective inhibitors, are among the most widely used drugs to treat pain and inflammation. However, clinical trials have revealed that these inhibitors predisposed patients to a significantly increased cardiovascular risk, consisting of thrombosis, hypertension, myocardial infarction, heart failure, and sudden cardiac death. Thus, microsomal prostaglandin E (PGE) synthase-1 (mPGES-1), the key terminal enzyme involved in the synthesis of inflammatory prostaglandin E2 (PGE2), and the four PGE2 receptors (EP1–4) have gained much attention as alternative targets for the development of novel analgesics. The cardiovascular consequences of targeting mPGES-1 and the PGE2 receptors are substantially studied. Inhibition of mPGES-1 has displayed a relatively innocuous or preferable cardiovascular profile. The modulation of the four EP receptors in cardiovascular system is diversely reported as well. In this review, we highlight the most recent advances from our and other studies on the regulation of PGE2, particularly mPGES-1 and the four PGE2 receptors, in cardiovascular function, with a particular emphasis on blood pressure regulation, atherosclerosis, thrombosis, and myocardial infarction. This might lead to new avenues to improve cardiovascular disease management strategies and to seek optimized anti-inflammatory therapeutic options.

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Overexpression of prostaglandin EP3 receptors activates calcineurin and promotes hypertrophy in the murine heart

Abstract: EP(3)-receptor-mediated signalling results in a significant anti-ischaemic action and activation of the pro-hypertrophic calcineurin signalling pathway, suggesting the involvement of the EP(3) subtype in both PGE(2)-mediated cardioprotection as well as cardiac hypertrophy.

Cited by 30 publications

References 36 publications

Prostaglandin E2 Reduces Cardiac Contractility via EP3 Receptor

Prostaglandin E2 Reduces Cardiac Contractility via EP3 Receptor

International Union of Basic and Clinical Pharmacology. LXXXIII: Classification of Prostanoid Receptors, Updating 15 Years of Progress

An Update of Microsomal Prostaglandin E Synthase‐1 and PGE₂ Receptors in Cardiovascular Health and Diseases

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Overexpression of prostaglandin EP3 receptors activates calcineurin and promotes hypertrophy in the murine heart

Abstract: EP(3)-receptor-mediated signalling results in a significant anti-ischaemic action and activation of the pro-hypertrophic calcineurin signalling pathway, suggesting the involvement of the EP(3) subtype in both PGE(2)-mediated cardioprotection as well as cardiac hypertrophy.

Cited by 30 publications

References 36 publications

Prostaglandin E2 Reduces Cardiac Contractility via EP3 Receptor

Prostaglandin E2 Reduces Cardiac Contractility via EP3 Receptor

International Union of Basic and Clinical Pharmacology. LXXXIII: Classification of Prostanoid Receptors, Updating 15 Years of Progress

An Update of Microsomal Prostaglandin E Synthase‐1 and PGE2 Receptors in Cardiovascular Health and Diseases

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Resources

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An Update of Microsomal Prostaglandin E Synthase‐1 and PGE₂ Receptors in Cardiovascular Health and Diseases