Too much of a good thing? Establishing a role of excessive RyR2 dephosphorylation in heart disease

Munro, Michelle L.; Jones, Peter P.

doi:10.1113/jp279569

Cited by 2 publications

(2 citation statements)

References 6 publications

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“…Asmuda et al demonstrated the expression of cTnT in the nucleus of neonatal cardiomyocytes, indicating that cardiac troponin and tropomyosin could have an important cellular function(s) beyond Ca 2+ regulation [ 34 ]. Although monolayer differentiated cardiomyocytes expressed RyR2 (Additional file 1 : Figure S5C), a protein channel responsible for balancing Ca 2+ homeostasis by effluxing excess of Ca 2+ from its Ca 2+ store sarcoplasmic reticulum (SR) upon stimulation [ 35 ], they failed to emit any Ca 2+ peaks when stimulated with Ca 2+ infusion. This could be possibly due to the RyR2 channels being not sensitive enough to respond to their external calcium cues.…”

Section: Discussionmentioning

confidence: 99%

Stage-specific regulation of signalling pathways to differentiate pluripotent stem cells to cardiomyocytes with ventricular lineage

et al. 2022

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Background Pluripotent stem cells (PSCs) can be an ideal source of differentiation of cardiomyocytes in vitro and during transplantation to induce cardiac regeneration. However, differentiation of PSCs into a heterogeneous population is associated with an increased incidence of arrhythmia following transplantation. We aimed to design a protocol to drive PSCs to a ventricular lineage by regulating Wnt and retinoic acid (RA) signalling pathways. Methods Mouse embryonic stem cells were cultured either in monolayers or three-dimensional hanging drop method to form embryonic bodies (EBs) and exposed to different treatments acting on Wnt and retinoic acid signalling. Samples were collected at different time points to analyse cardiomyocyte-specific markers by RT-PCR, flow cytometry and immunofluorescence. Results Treatment of monolayer and EBs with Wnt and RA signalling pathways and ascorbic acid, as a cardiac programming enhancer, resulted in the formation of an immature non-contractile cardiac population that expressed many of the putative markers of cardiac differentiation. The population exhibited upregulation of ventricular specific markers while suppressing the expression of pro-atrial and pro-sinoatrial markers. Differentiation of EBs resulted in early foetal like non-contractile ventricular cardiomyocytes with an inherent propensity to contract when stimulated. Conclusion Our results provide the first evidence of in vitro differentiation that mimics the embryonic morphogenesis towards ventricular specific cardiomyocytes through regulation of Wnt and RA signalling pathways.

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Section: Discussionmentioning

confidence: 99%

Stage-specific regulation of signalling pathways to differentiate pluripotent stem cells to cardiomyocytes with ventricular lineage

et al. 2022

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“…The highconductance intracellular Ca 2+ channel RyR2 is essential for the coupling of excitation and contraction in cardiac muscle [41]. Accordingly, increasing the magnitude of calcium flux through RyR2 is a critical element in increasing the force of contraction and consequently the amount of blood ejected from the heart per beat [42]. Phosphorylation of cardiac RyRs is an important modulatory mechanism of Sarcoplasmic reticulum(SR) Ca 2+ release characteristics [43].…”

Section: Interaction Of Cav3 and Ryr2mentioning

confidence: 99%

Induction of Caveolin-3/RyR2 By Liraglutide Ameliorates Diabetic Cardiomyopathy

Wang

et al. 2021

Preprint

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Background Liraglutide (LIRA), a Glucagon-like peptide-1 receptor agonist (GLP-1RA), showed potent cardioprotective effects with the mechanism remained incompletely understood. Caveolin-3 (Cav3) is the cardiomyocytes specific caveolae structural protein, decreased in the diabetic heart. Therefore, this study aimed to investigate whether LIRA exerts its effect on cardiac function in rats with type 2 diabetes mellitus (T2DM) via enhance Cav3 expression. Methods T2DM rats were used as study subjects and randomly divided into four groups: 1) CON group, 2) CON+L group, 3) DM group and 4) DM+L group. All rats received either saline or LIRA 0.2 mg/kg (by i.p injection) per day for 4 weeks. After the model was successfully established, cardiac function was determined by invasive hemodynamic evaluation methods. Immunohistochemistry and western blot were performed to understand the molecular mechanism between cardiac function and LIRA. Results Based on our results, DM group displayed higher blood glucose than Con group (20.57±2.75 mol/L vs. 4.34±0.21 mol/L), while blood glucose level in DM+L group was lower than DM group after received LIRA (10.36±1.84 mol/L). LVSP (91.39±4.98 mmHg), LV +dp/dtmax (4040.74±197.72 mmHg/s) were significantly reduced in DM group, and diabetic rats also exhibited reduced -dp/dtmax (2926.5±142.3 mmHg/s) and elevated LVEDP (10.87±0.83 mmHg). LIRA treatment showed a trend to enhance LVSP (110.76±5.61 mmHg) and ± dp/dtmax (5860.41±200.32 mmHg and 3996.8±179.3 mmHg), decreased LVEDP (7.23±0.58 mmHg). The expression of Cav3, eNOS and RyR2 was significantly decreased in the myocardium in DM group, which increased in DM+L group after LIRA administrated. Hemodynamic data showed DM rats exhibited impairment of myocardial function, while LIRA improved cardiac systolic and diastolic function, attenuate diabetic cardiomyopathy injury by improving Cav3/eNOS/NO signaling, reducing ROS level in cardiac tissues, and increasing interaction of Cav3 and ryanodine receptor 2 (RyR2). Conclusions Liraglutide ameliorates cardiac dysfunction in rats with type 2 diabetes mellitus via reducing ROS level in cardiac tissues, improving Cav3/eNOS/NO signaling and increasing interaction of Cav3 and RyR2. Keywords Type-2 diabetes Mellitus, liraglutide, caveolin-3, ryanodine receptor2, myocardial dysfunction

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Too much of a good thing? Establishing a role of excessive RyR2 dephosphorylation in heart disease

Cited by 2 publications

References 6 publications

Stage-specific regulation of signalling pathways to differentiate pluripotent stem cells to cardiomyocytes with ventricular lineage

Stage-specific regulation of signalling pathways to differentiate pluripotent stem cells to cardiomyocytes with ventricular lineage

Induction of Caveolin-3/RyR2 By Liraglutide Ameliorates Diabetic Cardiomyopathy

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