Complex functionality of protein phosphatase 1 isoforms in the heart

Liu, Ruijie

doi:10.1016/j.cellsig.2021.110059

Cited by 3 publications

(6 citation statements)

References 137 publications

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“…The phosphorylation of phosphatase inhibitor 1 ( Gergs et al, 2019 ) was observed to activate this protein, which then inhibited protein phosphatase 1, a major cardiac phosphatase ( Figure 1A ) ( Herzig and Neumann 2000 ), thus amplifying and possibly prolonging the effect of PKA on protein phosphorylation in the heart. Phosphatase 1 showed a highly complicated compartmentalisation in the heart ( Herzig and Neumann 2000 ; Liu, 2021 ), and thus histamine pathways might be fine-tuned. H 2 -histamine receptors not only increased phosphorylation via PKA but also via β-arrestin ( Figure 1A ) and other transducers, which finally increased the phosphorylation state and activity of downstream kinases, such as extracellular regulated receptor kinase 1/2 (ERK1/2) ( Figure 1A ) ( Luo et al, 2013 ) and death-associated protein kinase 2 (DAPK2) in neonatal rat cardiomyocytes ( Figure 1A ) ( Luo et al, 2013 ).…”

Section: Signal Transduction Of Cardiac Histamine Receptorsmentioning

confidence: 99%

The Roles of Cardiovascular H2-Histamine Receptors Under Normal and Pathophysiological Conditions

Neumann¹,

Kirchhefer²,

Dhein³

et al. 2021

Front. Pharmacol.

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This review addresses pharmacological, structural and functional relationships among H2-histamine receptors and H1-histamine receptors in the mammalian heart. The role of both receptors in the regulation of force and rhythm, including their electrophysiological effects on the mammalian heart, will then be discussed in context. The potential clinical role of cardiac H2-histamine-receptors in cardiac diseases will be examined. The use of H2-histamine receptor agonists to acutely increase the force of contraction will be discussed. Special attention will be paid to the potential role of cardiac H2-histamine receptors in the genesis of cardiac arrhythmias. Moreover, novel findings on the putative role of H2-histamine receptor antagonists in treating chronic heart failure in animal models and patients will be reviewed. Some limitations in our biochemical understanding of the cardiac role of H2-histamine receptors will be discussed. Recommendations for further basic and translational research on cardiac H2-histamine receptors will be offered. We will speculate whether new knowledge might lead to novel roles of H2-histamine receptors in cardiac disease and whether cardiomyocyte specific H2-histamine receptor agonists and antagonists should be developed.

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Section: Signal Transduction Of Cardiac Histamine Receptorsmentioning

confidence: 99%

The Roles of Cardiovascular H2-Histamine Receptors Under Normal and Pathophysiological Conditions

Neumann¹,

Kirchhefer²,

Dhein³

et al. 2021

Front. Pharmacol.

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“…Using TargetScan software, we predicted the potential target genes of miR-100-5p and selected PP-1 β as a candidate target gene. PP-1 β is one of the catalytic subunits of PP-1, which is the major isotype of serine/threonine phosphatase in cardiomyocytes and plays a pivotal role in regulating the phosphorylation of PLB at the Ser 16 site [ 38 ]. Accordingly, a luciferase experiment was performed to verify the interaction between PP-1 β and miR-100-5p using a dual-luciferase reporter plasmid containing wild-type (WT) or mutant PP-1 β 3' UTR sequence (Fig.…”

Section: Resultsmentioning

confidence: 99%

Exosomes secreted by endothelial cells derived from human induced pluripotent stem cells improve recovery from myocardial infarction in mice

Li,

Wang,

et al. 2023

Stem Cell Res Ther

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Background Human induced pluripotent stem cell-derived endothelial cells (hiPSC-ECs) exhibit the potential to repair the injured heart after myocardial infarction (MI) by promoting neovascularization and cardiomyocyte survival. However, because of the low cellular retention and poor engraftment efficacy, cell therapy of MI is partly mediated by exosomes secreted from the transplanted cells. In this study, we investigated whether exosomes secreted from hiPSC-ECs could become a promising acellular approach to repair the infarcted heart after MI and elucidated the underlying protective mechanism. Methods The hiPSC-ECs were differentiated, and exosomes were isolated in vitro. Then, hiPSC-EC exosomes were delivered by intramyocardial injection in a murine MI model in vivo. Echocardiography, combined with hemodynamic measurement, histological examination, Ca2+ transient and cell shortening assessment, and Western blot, was used to determine the protective effects of hiPSC-EC exosomes on the infarcted heart. Furthermore, microRNA sequencing, luciferase activity assay, and microRNA gain–loss function experiments were performed to investigate the enriched microRNA and its role in exosome-mediated effects. Results In vitro, the hiPSC-EC exosomes enhanced intracellular Ca2+ transients, increased ATP content, and improved cell survival to protect cardiomyocytes from oxygen–glucose deprivation injury. Congruously, hiPSC-EC exosome administration in vivo improved the myocardial contractile function and attenuated the harmful left ventricular remodeling after MI without increasing the frequency of arrhythmias. Mechanistically, the hiPSC-EC exosomes notably rescued the protein expression and function of the sarcoplasmic reticulum Ca2+ ATPase 2a (SERCA-2a) and ryanodine receptor 2 (RyR-2) to maintain intracellular Ca2+ homeostasis and increase cardiomyocyte contraction after MI. The microRNA sequencing showed that miR-100-5p was the most abundant microRNA in exosomes. miR-100-5p could target protein phosphatase 1β (PP-1β) to enhance phospholamban (PLB) phosphorylation at Ser16 and subsequent SERCA activity, which contributes to the hiPSC-EC exosome-exerted cytoprotective effects on maintaining intracellular Ca2+ homeostasis and promoting cardiomyocyte survival. Conclusion The hiPSC-EC exosomes maintain cardiomyocyte Ca2+ homeostasis to improve myocardial recovery after MI, which may provide an acellular therapeutic option for myocardial injury.

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“…It is well established that protein function is regulated by a fine equilibrium of protein phosphorylation, which depends on a dynamic balance of protein kinase and phosphatase activities [45]. PP-1, the main abundant serine/threonine phosphatase, plays a pivotal role in regulating protein dephosphorylation and has multiple Ca 2+ -cycling protein targets such as PLB [34]. A previous study has reported that PP-1β is the major catalytic subunit of PP-1 in the heart that could elevate PLB phosphorylation at Ser 16 to enhance Ca 2+ transient and cell shortening [34,46].…”

Section: Discussionmentioning

confidence: 99%

“…PP-1, the main abundant serine/threonine phosphatase, plays a pivotal role in regulating protein dephosphorylation and has multiple Ca 2+ -cycling protein targets such as PLB [34]. A previous study has reported that PP-1β is the major catalytic subunit of PP-1 in the heart that could elevate PLB phosphorylation at Ser 16 to enhance Ca 2+ transient and cell shortening [34,46]. Interestingly, in this study, we linked the inhibition of PP-1β to hiPSC-EC exosome-mediated Ca 2+ modulation and cardioprotective effects.…”

Section: Discussionmentioning

confidence: 99%

“…Through the TargetScan software, we predicated the potential target genes of miR-100-5p and selected PP-1β as a candidate target gene. PP-1β has been reported as one of the catalytic subunits of PP-1, which is the major isotype of serine/threonine phosphatase in cardiomyocytes and plays a pivotal role in regulating the phosphorylation of PLB at Ser 16 site [34]. Accordingly, luciferase experiment was performed to verify the interaction between PP-1β and miR-100-5p by using a dual-luciferase reporter plasmid containing WT or mutant PP-1β 3' UTR sequence (Fig.…”

Section: Hipsc-ecmentioning

confidence: 99%

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Exosomes secreted by endothelial cells derived from human induced pluripotent stem cells protect heart from myocardial infarction by modulating cardiomyocyte calcium homeostasis

Wang

et al. 2022

Preprint

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Background: Human induced pluripotent stem cell–derived endothelial cells (hiPSC-ECs) exhibit potential in repairing the injured heart after myocardial infarction (MI) by promoting neovascularization and cardiomyocyte survival. However, because of the low cellular retention and poor engraftment efficacy, cell therapy treatment of MI is in part mediated by exosomes secreted from the transplanted cells. We investigated whether exosomes secreted from hiPSC-ECs could become a promising acellular approach to repairing the infarcted heart after MI, and elucidated the underlying protective mechanism. Methods: hiPSC-ECs were differentiated and exosomes were isolated in vitro. Then, hiPSC-EC exosomes were delivered by intramyocardial injection in a murine MI model in vivo. Echocardiography, combined with hemodynamic measurement, histological examination, Ca2+ transient and cell shortening assessment, and western blot, was used to determine protective effects of hiPSC-EC exosomes on the infarcted heart. Furthermore, microRNA sequencing, luciferase activity assay, and microRNA gain–loss function experiments were performed to investigate the enriched microRNA and its role in exosome-mediated effects. Results: In vitro assessments demonstrated that hiPSC-EC exosomes could be taken up by cardiomyocytes and that they possess the capability to protect cardiomyocytes from oxygen–glucose deprivation injury by enhancing Ca2+ transients, increasing ATP content, and promoting cell survival. Congruously, hiPSC-EC exosomes administration in vivo not only improved myocardial contractile function but also attenuated the harmful left ventricular remodeling after MI. Mechanistically, hiPSC-EC exosomes notably rescued the protein expression and function of sarcoplasmic reticulum Ca2+ ATPase 2a (SERCA-2a) and ryanodine receptor 2 (RyR-2) to maintain intracellular Ca2+ homeostasis and increase cardiomyocyte contraction after MI. microRNA sequencing determined that miR-100-5p was the most abundant microRNA in exosomes, and miR-100-5p could target protein phosphatase 1β (PP-1β) to enhance the phosphorylation level of phospholamban (PLB) at Ser16 and subsequent SERCA activity, which contributes to the hiPSC-EC exosome–exerted cytoprotective effects on maintaining intracellular Ca2+ homeostasis and promoting cardiomyocyte survival. Conclusion: hiPSC-EC exosomes maintain cardiomyocyte Ca2+ homeostasis to improve myocardial recovery after MI, which may provide an acellular therapeutic option for myocardial injury. Keywords: hiPSC-ECs, exosomes, Ca2+ homeostasis, miR-100-5p

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Complex functionality of protein phosphatase 1 isoforms in the heart

Cited by 3 publications

References 137 publications

The Roles of Cardiovascular H2-Histamine Receptors Under Normal and Pathophysiological Conditions

The Roles of Cardiovascular H2-Histamine Receptors Under Normal and Pathophysiological Conditions

Exosomes secreted by endothelial cells derived from human induced pluripotent stem cells improve recovery from myocardial infarction in mice

Exosomes secreted by endothelial cells derived from human induced pluripotent stem cells protect heart from myocardial infarction by modulating cardiomyocyte calcium homeostasis

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