Hypoxia Produces Pro-arrhythmic Late Sodium Current in Cardiac Myocytes by SUMOylation of NaV1.5 Channels

Plant, Leigh D.; Xiong, Dazhi; Romero, Jesús G.; Dai, Hui; Goldstein, Steve A.N.

doi:10.1016/j.celrep.2020.01.025

Cited by 42 publications

(47 citation statements)

References 59 publications

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“…A ~2-fold change in CRMP2 SUMOylation was observed in sciatic nerve, dorsal horn and glabrous skin during neuropathic pain [ 92 ] suggesting that larger changes in HCN2 SUMOylation may be observed in subcellular compartments such as axons and terminals relative to somata. Additional ion channels are known to be SUMOylated including Kv4 [ 82 ], Kv11 [ 83 ], Kv7 [ 84 , 93 ], Kv2 [ 94 ], K2P1 [ 85 , 95 ], Kv1.5 [ 86 ], NaV1.2 [ 87 ] and NaV1.5 [ 96 ]. Their SUMOylation patterns have not yet been ascertained during chronic pain.…”

Section: Discussionmentioning

confidence: 99%

Changes in peripheral HCN2 channels during persistent inflammation

et al. 2021

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Nociceptor sensitization following nerve injury or inflammation leads to chronic pain. An increase in the nociceptor hyperpolarization-activated current, I h , is observed in many models of pathological pain. Pharmacological blockade of I h prevents the mechanical and thermal hypersensitivity that occurs during pathological pain. Alterations in the Hyperpolarization-activated Cyclic Nucleotidegated ion channel 2 (HCN2) mediate I h -dependent thermal and mechanical hyperalgesia. Limited knowledge exists regarding the nature of these changes during chronic inflammatory pain. Modifications in HCN2 expression and post-translational SUMOylation have been observed in the Complete Freund's Adjuvant (CFA) model of chronic inflammatory pain. Intra-plantar injection of CFA into the rat hindpaw induces unilateral hyperalgesia that is sustained for up to 14 days following injection. The hindpaw is innervated by primary afferents in lumbar DRG, L4-6. Adjustments in HCN2 expression and SUMOylation have been well-documented for L5 DRG during the first 7 days of CFAinduced inflammation. Here, we examine bilateral L4 and L6 DRG at day 1 and day 3 post-CFA. Using L4 and L6 DRG cryosections, HCN2 expression and SUMOylation were measured with immunohistochemistry and proximity ligation assays, respectively. Our findings indicate that intra-plantar injection of CFA elicited a bilateral increase in HCN2 expression in L4 and L6 DRG at day 1, but not day 3, and enhanced HCN2 SUMOylation in ipsilateral L6 DRG at day 1 and day 3. Changes in HCN2 expression and SUMOylation were transient over this time course. Our study suggests that HCN2 is regulated by multiple mechanisms during CFA-induced inflammation.

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Section: Discussionmentioning

confidence: 99%

Changes in peripheral HCN2 channels during persistent inflammation

et al. 2021

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“…Perhaps the phenotype of Q1909R becomes manifest only in specific circumstances, which may not be apparent in healthy sedentary laboratory animals. For instance, a bevy of other cellular factors and conditions have been shown to upregulate late Na + current( 42 , 43 ), including heart failure ( 44 ), hypoxia ( 45 , 46 ), reactive oxygen species ( 45 ), CaMKII-dependent phosphorylation ( 47 , 48 ), and altered interaction with other regulatory proteins ( 49 , 50 ). It is possible that some of these processes may be linked to FHF modulation of Na V 1.5.…”

Section: Discussionmentioning

confidence: 99%

Fibroblast growth factor homologous factors tune arrhythmogenic late NaV1.5 current in calmodulin binding–deficient channels

Abrams¹,

Roybal²,

Chakouri³

et al. 2020

JCI Insight

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The Ca 2+ -binding protein calmodulin has emerged as a pivotal player in tuning Na + channel function, although its impact in vivo remains to be resolved. Here, we identify the role of calmodulin and the Na V 1.5 interactome in regulating late Na + current in cardiomyocytes. We created transgenic mice with cardiac-specific expression of human Na V 1.5 channels with alanine substitutions for the IQ motif (IQ/AA). The mutations rendered the channels incapable of binding calmodulin to the C-terminus. The IQ/AA transgenic mice exhibited normal ventricular repolarization without arrhythmias and an absence of increased late Na + current. In comparison, transgenic mice expressing a lidocaine-resistant (F1759A) human Na V 1.5 demonstrated increased late Na + current and prolonged repolarization in cardiomyocytes, with spontaneous arrhythmias. To determine regulatory factors that prevent late Na + current for the IQ/AA mutant channel, we considered fibroblast growth factor homologous factors (FHFs), which are within the Na V 1.5 proteomic subdomain shown by proximity labeling in transgenic mice expressing Na V 1.5 conjugated to ascorbate peroxidase. We found that FGF13 diminished late current of the IQ/AA but not F1759A mutant cardiomyocytes, suggesting that endogenous FHFs may serve to prevent late Na + current in mouse cardiomyocytes. Leveraging endogenous mechanisms may furnish an alternative avenue for developing novel pharmacology that selectively blunts late Na + current.

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“…Together, these abnormalities can lead to reduced CV and smaller λ, and/or increased heterogeneity in conduction. Moreover, hypoxia can increase the late component of I Na through SUMOlysation [27] , leading to prolonged APDs that can predispose to reentry.…”

Section: The Hypothesismentioning

confidence: 99%

COVID-19: Electrophysiological mechanisms underlying sudden cardiac death during exercise with facemasks

Lee¹,

Liu

et al. 2020

Medical Hypotheses

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The mandatory use of facemasks is a public health measure implemented by various countries in response to the novel coronavirus disease 19 (COVID-19) pandemic. However, there have been case reports of sudden cardiac death (SCD) with the wearing of facemasks during exercise. In this paper, we hypothesize that exercise with facemasks may increase the risk of ventricular tachycardia/ventricular fibrillation (VT/VF) leading to SCD via the development of acute and/or intermittent hypoxia and hypercapnia. We discuss the potential underlying mechanisms including increases in adrenergic stimulation and oxidative stress leading to electrophysiological abnormalities that promote arrhythmias via non-reentrant and reentrant mechanisms. Given the interplay of multiple variables contributing to the increased arrhythmic risk, we advise avoidance of a facemask during high intensity exercise, or if wearing of a mask is mandatory, exercise intensity should remain low to avoid precipitation of lethal arrhythmias. However, we cannot exclude the possibility of an arrhythmic substrate even with low intensity exercise especially in those with established chronic cardiovascular disease in whom baseline electrophysiological abnormalities may be found.

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Hypoxia Produces Pro-arrhythmic Late Sodium Current in Cardiac Myocytes by SUMOylation of NaV1.5 Channels

Cited by 42 publications

References 59 publications

Changes in peripheral HCN2 channels during persistent inflammation

Changes in peripheral HCN2 channels during persistent inflammation

Fibroblast growth factor homologous factors tune arrhythmogenic late NaV1.5 current in calmodulin binding–deficient channels

COVID-19: Electrophysiological mechanisms underlying sudden cardiac death during exercise with facemasks

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