Overexpression of prostaglandin E2 EP4 receptor improves cardiac function after myocardial infarction

Bryson, Timothy D; Gu, Xiaosong; Khalil, Remonda M; Khan, Safa; Zhu, Liping; Peterson, Edward L.; Yang, Xiao‐Ping; Harding, Pamela

doi:10.1016/j.yjmcc.2018.03.005

Cited by 29 publications

(26 citation statements)

References 34 publications

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“…We further build on the findings of these past studies that link mitochondrial calcium accumulation with ROS production alongside the induction of MPT, bioenergetic collapse and necrosis both in cultured cardiomyocytes and in vivo. Importantly the work presented here also demonstrates that these pathways can be pharmacologically modulated through PGE1-induced EP4 activation, which work from us and others, has been shown to be cardioprotective (Field et al, 2018;Martens et al, 2020;Bryson et al, 2018). While a previous study has demonstrated that Bnip3 phosphorylation inhibits its interactions with OPA-1, we provide mechanistic evidence both in vivo and in cardiomyocytes that misoprostol activates the EP4 receptor and PKA, resulting in an inhibitory phosphorylation of Bnip3's TM domain at Thr-181.…”

Section: Discussionsupporting

confidence: 64%

“…Interestingly, previous work has demonstrated that prostaglandin (PG) signalling through the PG EP4 receptor, a G-protein coupled receptor classically associated with enhanced protein kinase A (PKA) activity, improves cardiac function in mice following MI (Bryson et al, 2018). Furthermore, overexpression of the EP3 receptor, known to reduce PKA activity, is deleterious in the murine heart (Bryson et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

“…Although generally regarded as pro-inflammatory, prostaglandin E1 (PGE1) has also been associated with the resolution of inflammation, T cell inhibition, and wound healing (Lanefelt et al , 1983; Syeda et al , 2012; Baker et al , 1981). Interestingly, previous work has demonstrated that prostaglandin signalling through the EP4 receptor, a G-protein coupled receptor classically associated with enhanced protein kinase A (PKA) activity, improves cardiac function in mice following infarction (Bryson et al , 2018). Furthermore, overexpression of the EP3 receptor, known to reduce PKA activity, is deleterious in the murine heart (Bryson et al , 2020).…”

Section: Introductionmentioning

confidence: 99%

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Misoprostol Treatment Prevents Hypoxia-Induced Cardiac Dysfunction Through a 14-3-3 and PKA regulatory motif on Bnip3

Martens

Seshadri

Nguyen

et al. 2020

Preprint

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Systemic hypoxia, a major complication associated with reduced gestational time, affects more 60% of preterm infants and is a known driver of hypoxia-induced Bcl-2-like 19kDa-interacting protein 3 (Bnip3) expression in the neonatal heart. At the level of the cardiomyocyte, Bnip3 activity plays a prominent role in the evolution of necrotic cell death, disrupting subcellular calcium homeostasis and initiating mitochondrial permeability transition (MPT). Emerging evidence suggests both a cardioprotective role for protein kinase A (PKA) through stimulatory prostaglandin (PG) E1 signalling during prolonged periods of hypoxia, and a cytoprotective role for Bnip3 phosphorylation, indicating that post-translational modifications of Bnip3 may be a point of convergence for these two protective pathways. Using a combination of in vivo and multiple cell models, including human iPSC-derived cardiomyocytes, we tested if the PGE1 analogue misoprostol is cardioprotective during neonatal hypoxic injury by altering the phosphorylation status of Bnip3. Here we report that hypoxia exposure significantly increases Bnip3 expression, mitochondrial-fragmentation, -ROS, -calcium accumulation and -permeability transition, while reducing mitochondrial membrane potential, all of which were restored to control levels with the addition of misoprostol, despite elevated Bnip3 protein expression. Through both gain- and loss-of-function genetic studies we further show that misoprostol-induced protection directly affects Bnip3, preventing mitochondrial perturbations. We demonstrate that this is a result of PG EP4 receptor signalling, PKA activation, and direct Bnip3 phosphorylation at threonine-181. Furthermore, when this PKA phosphorylation site within Bnip3 is neutralized, the protective misoprostol effect is lost. We also provide evidence that misoprostol traffics Bnip3 away from the ER through a physical interaction with 14-3-3β, thereby preventing aberrant ER calcium release and MPT. In vivo studies further demonstrate that misoprostol treatment increases Bnip3 phosphorylation at threonine-181 in the mouse heart, preventing hypoxia-induced reductions in cardiac ejection fraction and fractional shortening. Taken together, our results demonstrate a foundational role for Bnip3 phosphorylation in the molecular regulation of cardiomyocyte contractile and metabolic dysfunction and identifies EP4 signaling as a potential pharmacological mechanism to prevent hypoxia-induced neonatal cardiac injury.Graphical Abstract

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Section: Discussionsupporting

confidence: 64%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Misoprostol Treatment Prevents Hypoxia-Induced Cardiac Dysfunction Through a 14-3-3 and PKA regulatory motif on Bnip3

Martens

Seshadri

Nguyen

et al. 2020

Preprint

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“…Western blot (WB) and real‐time PCR ( RT‐PCR) were carried out as previously described . Antibodies for NLRP3 and ASC were purchased from Santa Cruz Technology (Santa Cruz, CA).…”

Section: Methodsmentioning

confidence: 99%

Gypenosides improve diabetic cardiomyopathy by inhibiting ROS‐mediated NLRP3 inflammasome activation

Zhang

Chen

Zong

et al. 2018

J Cellular Molecular Medi

118

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NLRP3 inflammasome activation plays an important role in diabetic cardiomyopathy (DCM), which may relate to excessive production of reactive oxygen species (ROS). Gypenosides (Gps), the major ingredients of Gynostemma pentaphylla (Thunb.) Makino, have exerted the properties of anti‐hyperglycaemia and anti‐inflammation, but whether Gps improve myocardial damage and the mechanism remains unclear. Here, we found that high glucose (HG) induced myocardial damage by activating the NLRP3 inflammasome and then promoting IL‐1β and IL‐18 secretion in H9C2 cells and NRVMs. Meanwhile, HG elevated the production of ROS, which was vital to NLRP3 inflammasome activation. Moreover, the ROS activated the NLRP3 inflammasome mainly by cytochrome c influx into the cytoplasm and binding to NLRP3. Inhibition of ROS and cytochrome c dramatically down‐regulated NLRP3 inflammasome activation and improved the cardiomyocyte damage induced by HG, which was also detected in cells treated by Gps. Furthermore, Gps also reduced the levels of the C‐reactive proteins (CRPs), IL‐1β and IL‐18, inhibited NLRP3 inflammasome activation and consequently improved myocardial damage in vivo. These findings provide a mechanism that ROS induced by HG activates the NLRP3 inflammasome by cytochrome c binding to NLRP3 and that Gps may be potential and effective drugs for DCM via the inhibition of ROS‐mediated NLRP3 inflammasome activation.

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“…Therefore, the stimulation of prostaglandin EP4 receptor by PGE 2 in an I/R model induces cardioprotective effects through the increase in IL10 secretion and inhibition of TNFα [ 67 ]. Gene therapy overexpressing prostaglandin EP4 receptor in mice subjected to MI restores cardiac function and reduces hypertrophy and fibrosis [ 46 ]. In addition, prostaglandin EP3 receptor selective activation reduces the infarct size post-MI [ 47 ].…”

Section: G Protein-coupled Receptors (Gpcrs)mentioning

confidence: 99%

Cardiac cAMP-PKA Signaling Compartmentalization in Myocardial Infarction

Colombe

Pidoux

2021

Cells

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Under physiological conditions, cAMP signaling plays a key role in the regulation of cardiac function. Activation of this intracellular signaling pathway mirrors cardiomyocyte adaptation to various extracellular stimuli. Extracellular ligand binding to seven-transmembrane receptors (also known as GPCRs) with G proteins and adenylyl cyclases (ACs) modulate the intracellular cAMP content. Subsequently, this second messenger triggers activation of specific intracellular downstream effectors that ensure a proper cellular response. Therefore, it is essential for the cell to keep the cAMP signaling highly regulated in space and time. The temporal regulation depends on the activity of ACs and phosphodiesterases. By scaffolding key components of the cAMP signaling machinery, A-kinase anchoring proteins (AKAPs) coordinate both the spatial and temporal regulation. Myocardial infarction is one of the major causes of death in industrialized countries and is characterized by a prolonged cardiac ischemia. This leads to irreversible cardiomyocyte death and impairs cardiac function. Regardless of its causes, a chronic activation of cardiac cAMP signaling is established to compensate this loss. While this adaptation is primarily beneficial for contractile function, it turns out, in the long run, to be deleterious. This review compiles current knowledge about cardiac cAMP compartmentalization under physiological conditions and post-myocardial infarction when it appears to be profoundly impaired.

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Overexpression of prostaglandin E2 EP4 receptor improves cardiac function after myocardial infarction

Abstract: Overexpression of EP4 improves cardiac function post MI. This may be mediated through reductions in adverse cardiac remodeling or via inhibition of cytokine/chemokine production.

Cited by 29 publications

References 34 publications

Misoprostol Treatment Prevents Hypoxia-Induced Cardiac Dysfunction Through a 14-3-3 and PKA regulatory motif on Bnip3

Misoprostol Treatment Prevents Hypoxia-Induced Cardiac Dysfunction Through a 14-3-3 and PKA regulatory motif on Bnip3

Gypenosides improve diabetic cardiomyopathy by inhibiting ROS‐mediated NLRP3 inflammasome activation

Cardiac cAMP-PKA Signaling Compartmentalization in Myocardial Infarction

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