Nitric oxide regulates cardiac intracellular Na+ and Ca2+ by modulating Na/K ATPase via PKCε and phospholemman-dependent mechanism

Pavlović, Davor; Hall, Andrew; Kennington, Erika; Aughton, Karen; Boguslavskyi, Andrii; Fuller, William; Despa, Sanda; Bers, Donald M.; Shattock, Michael J.

doi:10.1016/j.yjmcc.2013.04.013

Cited by 35 publications

(37 citation statements)

References 48 publications

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“…24 Under unstimulated conditions, PLM in WT myocytes is up to 40% phosphorylated. 10 This basal phosphorylation is obviously absent in PLM 3SA mice.…”

Section: Resultsmentioning

confidence: 98%

Cardiac hypertrophy in mice expressing unphosphorylatable phospholemman

Boguslavskyi

Pavlović

Aughton

et al. 2014

Cardiovascular Research

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AimsElevation of intracellular Na in the failing myocardium contributes to contractile dysfunction, the negative force–frequency relationship, and arrhythmias. Although phospholemman (PLM) is recognized to form the link between signalling pathways and Na/K pump activity, the possibility that defects in its regulation contribute to elevation of intracellular Na has not been investigated. Our aim was to test the hypothesis that the prevention of PLM phosphorylation in a PLM3SA knock-in mouse (in which PLM has been rendered unphosphorylatable) will exacerbate cardiac hypertrophy and cellular Na overload. Testing this hypothesis should determine whether changes in PLM phosphorylation are simply bystander effects or are causally involved in disease progression.Methods and resultsIn wild-type (WT) mice, aortic constriction resulted in hypophosphorylation of PLM with no change in Na/K pump expression. This under-phosphorylation of PLM occurred at 3 days post-banding and was associated with a progressive decline in Na/K pump current and elevation of [Na]i. Echocardiography, morphometry, and pressure-volume (PV) catheterization confirmed remodelling, dilation, and contractile dysfunction, respectively. In PLM3SA mice, expression of Na/K ATPase was increased and PLM decreased such that net Na/K pump current under quiescent conditions was unchanged (cf. WT myocytes); [Na+]i was increased and forward-mode Na/Ca exchanger was reduced in paced PLM3SA myocytes. Cardiac hypertrophy and Na/K pump inhibition were significantly exacerbated in banded PLM3SA mice compared with banded WT.ConclusionsDecreased phosphorylation of PLM reduces Na/K pump activity and exacerbates Na overload, contractile dysfunction, and adverse remodelling following aortic constriction in mice. This suggests a novel therapeutic target for the treatment of heart failure.

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“…24 Under unstimulated conditions, PLM in WT myocytes is up to 40% phosphorylated. 10 This basal phosphorylation is obviously absent in PLM 3SA mice.…”

Section: Resultsmentioning

confidence: 98%

Cardiac hypertrophy in mice expressing unphosphorylatable phospholemman

Boguslavskyi

Pavlović

Aughton

et al. 2014

Cardiovascular Research

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“…have shown that NO stimulates NKA via PKC‐mediated PLM phosphorylation (Pavlovic et al . ). Whether similar pathways exist in the vasculature is yet to be determined.…”

Section: The Na+/ca2+ Exchanger – Structure Function and Regulationmentioning

confidence: 97%

Na⁺/Ca²⁺ exchange and Na⁺/K⁺‐ATPase in the heart

Shattock

Ottolia

Bers

et al. 2015

The Journal of Physiology

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166

157

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This paper is the third in a series of reviews published in this issue resulting from the University of California Davis Cardiovascular Symposium 2014: Systems approach to understanding cardiac excitation–contraction coupling and arrhythmias: Na+ channel and Na+ transport. The goal of the symposium was to bring together experts in the field to discuss points of consensus and controversy on the topic of sodium in the heart. The present review focuses on cardiac Na+/Ca2+ exchange (NCX) and Na+/K+-ATPase (NKA). While the relevance of Ca2+ homeostasis in cardiac function has been extensively investigated, the role of Na+ regulation in shaping heart function is often overlooked. Small changes in the cytoplasmic Na+ content have multiple effects on the heart by influencing intracellular Ca2+ and pH levels thereby modulating heart contractility. Therefore it is essential for heart cells to maintain Na+ homeostasis. Among the proteins that accomplish this task are the Na+/Ca2+ exchanger (NCX) and the Na+/K+ pump (NKA). By transporting three Na+ ions into the cytoplasm in exchange for one Ca2+ moved out, NCX is one of the main Na+ influx mechanisms in cardiomyocytes. Acting in the opposite direction, NKA moves Na+ ions from the cytoplasm to the extracellular space against their gradient by utilizing the energy released from ATP hydrolysis. A fine balance between these two processes controls the net amount of intracellular Na+ and aberrations in either of these two systems can have a large impact on cardiac contractility. Due to the relevant role of these two proteins in Na+ homeostasis, the emphasis of this review is on recent developments regarding the cardiac Na+/Ca2+ exchanger (NCX1) and Na+/K+ pump and the controversies that still persist in the field.

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“…PKA-dependent phosphorylation of Ser68 and PKC-dependent phosphorylation of Ser63 or Ser68 on phospholemman reduce its inhibition of the Na + -K + -ATPase [76]. PP1, but not PP2A, dephosphorylates phospholemman at Ser68 and this is controlled by the PP1 inhibitor I-1 [77].…”

Section: Altered Regulation Of Cardiac Electrophysiology and Contrmentioning

confidence: 99%

Serine/Threonine Phosphatases in Atrial Fibrillation

Heijman

Ghezelbash

Wehrens

et al. 2017

Journal of Molecular and Cellular Cardiology

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Serine/threonine protein phosphatases control dephosphorylation of numerous cardiac proteins, including a variety of ion channels and calcium-handling proteins, thereby providing precise post-translational regulation of cardiac electrophysiology and function. Accordingly, dysfunction of this regulation can contribute to the initiation, maintenance and progression of cardiac arrhythmias. Atrial fibrillation (AF) is the most common heart rhythm disorder and is characterized by electrical, autonomic, calcium-handling, contractile, and structural remodeling, which include, among other things, changes in the phosphorylation status of a wide range of proteins. Here, we review AF-associated alterations in the phosphorylation of atrial ion channels, calcium-handling and contractile proteins, and their role in AF-pathophysiology. We highlight the mechanisms controlling the phosphorylation of these proteins and focus on the role of altered dephosphorylation via local type-1, type-2A and type-2B phosphatases (PP1, PP2A, and PP2B, also known as calcineurin, respectively). Finally, we discuss the challenges for phosphatase research, potential therapeutic significance of altered phosphatase-mediated protein dephosphorylation in AF, as well as future directions.

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Nitric oxide regulates cardiac intracellular Na+ and Ca2+ by modulating Na/K ATPase via PKCε and phospholemman-dependent mechanism

Cited by 35 publications

References 48 publications

Cardiac hypertrophy in mice expressing unphosphorylatable phospholemman

Cardiac hypertrophy in mice expressing unphosphorylatable phospholemman

Na⁺/Ca²⁺ exchange and Na⁺/K⁺‐ATPase in the heart

Serine/Threonine Phosphatases in Atrial Fibrillation

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Nitric oxide regulates cardiac intracellular Na+ and Ca2+ by modulating Na/K ATPase via PKCε and phospholemman-dependent mechanism

Cited by 35 publications

References 48 publications

Cardiac hypertrophy in mice expressing unphosphorylatable phospholemman

Cardiac hypertrophy in mice expressing unphosphorylatable phospholemman

Na+/Ca2+ exchange and Na+/K+‐ATPase in the heart

Serine/Threonine Phosphatases in Atrial Fibrillation

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Na⁺/Ca²⁺ exchange and Na⁺/K⁺‐ATPase in the heart