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Review

Modulation of Redox-Sensitive Cardiac Ion Channels

by
Razan Orfali
1,*,
Al Hassan Gamal El-Din
2,
Varnika Karthick
2,
Elisanjer Lamis
2,
Vanna Xiao
2,
Alena Ramanishka
2,
Abdullah Alwatban
1,
Osama Alkhamees
1,
Ali Alaseem
1,
Young-Woo Nam
2 and
Miao Zhang
2
1
Department of Pharmacology, College of Medicine, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh 13317, Saudi Arabia
2
Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Irvine, CA 92618, USA
*
Author to whom correspondence should be addressed.
Antioxidants 2025, 14(7), 836; https://doi.org/10.3390/antiox14070836
Submission received: 4 June 2025 / Revised: 30 June 2025 / Accepted: 5 July 2025 / Published: 8 July 2025
(This article belongs to the Special Issue New Insight into Redox Homeostasis and Oxidative Stress in Health and Disease: Focus on Cardiac and Vascular Function)
Browse Figures
Versions Notes

Abstract

Redox regulation is crucial for the cardiac action potential, coordinating the sodium-driven depolarization, calcium-mediated plateau formation, and potassium-dependent repolarization processes required for proper heart function. Under physiological conditions, low-level reactive oxygen species (ROS), generated by mitochondria and membrane oxidases, adjust ion channel function and support excitation–contraction coupling. However, when ROS accumulate, they modify a variety of important channel proteins in cardiomyocytes, which commonly results in reducing potassium currents, enhancing sodium and calcium influx, and enhancing intracellular calcium release. These redox-driven alterations disrupt the cardiac rhythm, promote after-depolarizations, impair contractile force, and accelerate the development of heart diseases. Experimental models demonstrate that oxidizing agents reduce repolarizing currents, whereas reducing systems restore normal channel activity. Similarly, oxidative modifications of calcium-handling proteins amplify sarcoplasmic reticulum release and diastolic calcium leak. Understanding the precise redox-dependent modifications of cardiac ion channels would guide new possibilities for targeted therapies aimed at restoring electrophysiological homeostasis under oxidative stress, potentially alleviating myocardial infarction and cardiovascular dysfunction.

Graphical Abstract

1. Introduction

Oxidative stress contributes to the pathobiology of many human diseases, including cardiovascular disorders, neurodegenerative diseases, and metabolic syndromes [1]. Enzymatic and nonenzymatic processes can produce reactive oxygen species (ROS) [2]. ROS are chemically reactive molecules containing oxygen, such as superoxide anions, hydrogen peroxide, and hydroxyl radicals, that arise predominantly as natural byproducts of cellular aerobic metabolism and play key roles in cell signaling and homeostasis [3]. Under normal conditions, ROS are present in small amounts and are essential for regular cellular and mitochondrial functions. Although ROS aid in signaling processes that maintain cellular health and activity, excessive ROS levels often cause severe intracellular damage to cells and, ultimately, entire tissues [2,4,5,6]. Excessive oxidative stress can initiate a cycle of inflammation and further ROS production, thereby worsening disease states [7]. In cardiac tissue, ROS are vital for maintaining cellular homeostasis by regulating cell proliferation, differentiation, and excitation–contraction coupling [8,9]. However, an overproduction of ROS disrupts this balance, leading to oxidative stress that causes cellular and molecular damage, and, ultimately, impaired cardiac function [10].
The heart functions as a biological mechanical pump, ensuring sufficient blood delivery to the body’s organs. Its ability to pump blood depends on the highly coordinated interactions of various cell types [11]. Connective tissue cells provide structural integrity, valve-forming cells construct the heart’s essential atrioventricular and semilunar valves, and cardiomyocytes produce the contractile force necessary for blood circulation [12]. Cardiac function depends on two connected properties: excitability, by which myocytes generate and propagate action potentials, and contractility, where actin–myosin sliding produces force. Tight coupling of these processes underlies the rhythmic pumping, and any disruption can precipitate arrhythmia or pump failure (i.e., heart failure) [13,14,15]. At the cellular level, cardiac excitability arises from a uniquely coordinated process in which ion channels, specialized molecular gates, open and close in a precise sequence, dictating the rhythmic contractions essential for human life (Figure 1) [16,17,18]. Furthermore, the imbalance in Ca2+ regulation in the heart significantly contributes to contractile dysfunction and the emergence of irregular heart rhythms within the failing myocardium. Such dysregulation arises from pathological alterations in the expression and activity of a complex group of Ca2+-binding proteins, ion channels, and enzymes, which become increasingly elucidated [19,20]. Additionally, excessive production of ROS exacerbates this imbalance, leading to oxidative stress that induces extensive cellular and molecular damage [21]. Most notably, excessive ROS can cause significant changes in the natural double-stranded DNA structure by oxidizing the nitrogenous base guanine into 8-oxoguanine, inducing a cascade of biological mechanisms that can result in apoptosis. Moreover, such cardiac cellular damage ultimately leads to impaired cardiac function [22,23,24]. The redox-sensitive cardiac ion channels respond dynamically to the cellular redox state as critical links between oxidative stress and alterations in cardiac electrophysiology [13]. Understanding the regulation of these channels could offer a clear framework for designing targeted therapies that protect or restore channel function under oxidative challenge.

2. Ion Channel Basis of Cardiac Excitation and Conduction

Under physiological conditions, the heart contracts and relaxes at approximately 60 beats per minute. Disruption of this regular rhythm for even a few minutes induces tissue hypoxia, leading to the irreversible injury of vital organs, including the myocardium, and may precipitate sudden cardiac death (SCD) [16,17,26]. The coordinated contraction of the atria and ventricles depends on both rapid action-potential propagation and efficient cell-to-cell coupling (Figure 1) [27,28]. Gap-junctional communication via Connexin43 supports the nearly prompt spread of depolarization, but the redox-sensitive phosphorylation of Connexin43 can slow conduction and promote arrhythmias [29]. This conduction system must remain flexible, capable of rapid heart-rate adjustments, and regulated by autonomic input. Underlying these mechanical events are action potentials (APs), the essential bioelectrical signals that trigger myocardial excitation and contraction [18,30]. The cardiac action potentials are fundamental to myocardial excitation and contraction. Unlike the brief action potentials in neurons and skeletal muscle fibers, cardiac myocytes exhibit a characteristic plateau phase in contractile cells (atria and ventricles) (Figure 1) and spontaneous, rhythmic firing in pacemaker cells (sinoatrial (SA) node [17,18]. These distinctive properties arise from the coordinated activity of voltage-gated ion channels involving sodium (Na+), calcium (Ca2+), and potassium (K+) (Table 1) [16,17].
In contractile myocytes, Phase 0 depolarization is driven by rapid Na+ influx through INa, while the plateau phase (Phase 2) results from sustained Ca2+ entry through L-type Ca2+ channels, facilitating excitation–contraction coupling. Repolarization (Phases 1–3) occurs as Na+ and Ca2+ channels are inactivated and multiple K+ currents, including the delayed rectifier K+ currents (IKr, IKs), restore the membrane potential [17,31,32] (Table 1) (Figure 1). The refractory period prevents tetanic contractions and maintains rhythmic pumping. In the SA node, the gradual depolarization during Phase 4 (unstable resting membrane potential) is mediated by the “funny” current (If) and transient T-type Ca2+ channels, enabling automaticity [18,33,34,35]. Sympathetic stimulation increases the rate of depolarization by enhancing If and Ca2+ currents, whereas parasympathetic activity slows it through muscarinic receptor-driven K+ efflux [18,36]. Impulses generated in the SA node propagate through the conduction system (AV node, Bundle of His, and Purkinje fibers) to synchronize atrial and ventricular contraction. While many studies have linked oxidative stress to cardiac pathology, growing evidence suggests that the redox regulation of ion channels can significantly influence action potential dynamics and may offer novel therapeutic targets [8,22,23,37].
Table 1. Main cardiac ion currents and their biophysical roles in action potential phases.
Table 1. Main cardiac ion currents and their biophysical roles in action potential phases.
Ion CurrentIon CarriedPrincipal Subunit (s)Physiological RoleReference(s)
INaNa+SCN5ARapid depolarization (Phase 0) and impulse conduction[38]
ICa,LCa2+CACNLIA1Plateau (Phase 2) and Ca2+ entry for excitation–contraction[39,40,41]
Ito1K+Kv1.2, Kv1.4
Kv1.5, Kv2.1
Kv4.2, Kv4.3		Early repolarization (Phase 1), spike-and-dome morphology[32,42]
Ito2K+—Calcium-activated early repolarization[32]
IKurK+Kv1.5Ultrarapid repolarization controls atrial AP duration[43]
IKrK+(hERG)
Kv11.1		Rapid delayed repolarization (Phase 3)[44]
IKsK+Kv7.1(KvLQT1) + KCNE1Slow delayed repolarization (Phase 3); repolarization reserve[45]
IK1K+Kir2Maintains resting potential (Phase 4) and final repolarization[46]

3. Redox Biology in Cardiomyocytes

The heart consumes more oxygen than any other organ. This demand can rise several-fold with increased workload, making it primarily dependent on redox signaling to adjust contractile force acutely and remodel structure constantly [47]. In cardiomyocytes, the primary reactive oxygen species in cardiac cells include the superoxide anion (O2·−), singlet oxygen (O2·), hydrogen peroxide (H2O2), the hydroxyl radical (OH·), and hypochlorous acid (HOCl) [10,12,13,24]. Key enzymatic sources of oxidative stress in the cardiovascular system are xanthine oxidoreductase (XOR), NADPH oxidases, nitric oxide synthases (NOS), mitochondrial electron-transport chain complexes, and hemoglobin [48,49]. Figure 2 illustrates these pathways: Mitochondrial electron leakage produces most superoxide, while cytosolic enzymes further amplify ROS pools. Adding a single electron to molecular oxygen yields the superoxide radical; because mitochondria use the majority of cellular O2 for respiration, most superoxide is produced within the mitochondrial matrix [13]. Mitochondria act as energy generators and signaling centers, using ROS and calcium flux to match contraction to demand. At physiological levels, ROS act as second messengers modulating kinases, transcription factors, and ion channels to adapt cardiac output [4,50,51]. Particularly, Connexin43 hemichannels respond to oxidation: The oxidative modification of critical cysteines disrupts gap-junctional conductance, slowing conduction during ischemia [52,53]. However, the exact redox-sensing mechanisms remain incompletely defined, and some studies report conflicting effects depending on ROS type and cellular setting [54]. When ROS overcome antioxidant defenses, superoxide dismutase (SOD), catalase, and glutathione peroxidase, the resulting oxidative stress triggers lipid peroxidation, protein carbonylation, and DNA damage, provoking inflammation and further ROS generation [55,56]. Critically, most studies rely on high-dose exogenous oxidants, highlighting the need for in vivo models to confirm physiological relevance [57]. Cardiomyocytes ultimately maintain mitochondrial integrity through quality-control mechanisms, such as mitophagy and proteostasis, that can be enhanced by exercise, caloric restriction, or targeted therapies. These interventions reduce oxidative damage and preserve cardiac function [58].

3.1. Antioxidant Defense Mechanisms in Cardiomyocytes

Cardiomyocytes rely on both enzymatic and nonenzymatic systems, such as small-molecule antioxidants, to counteract free-radical damage. Key enzymes include superoxide dismutase (SOD) [59], glutathione peroxidase (GPx) [60], and catalase (CAT) [61]. Small-molecule antioxidants include ascorbic acid (vitamin C), α-tocopherol (vitamin E), glutathione (GSH), carotenoids, and flavonoids [62]. Dietary compounds such as polyunsaturated fatty acids (PUFAs) also modulate cardiac contractility and excitability by enhancing antioxidant capacity [63]. Under resting conditions, a dynamic equilibrium exists between oxidant production and antioxidant activity. For instance, GPx detoxifies peroxides using GSH as a cofactor, converting it to its oxidized form (GSSG) in the process [64]. Figure 3 illustrates how antioxidants work together to maintain redox balance in cardiac cells [13].

3.2. Redox Regulation and Cardiac Disease

Redox homeostasis plays a critical role in maintaining cardiac function. In physiological conditions, reactive oxygen species act as signaling molecules that regulate processes such as myocardial contraction [8] and gene expression [65]. This redox signaling is crucial for maintaining cardiac homeostasis. However, the disruption of this balance, characterized by excessive ROS production or impaired antioxidant defenses, leads to oxidative stress, which contributes to the pathogenesis of various cardiac disorders [23,24,66]. Such oxidative stress is associated with conditions like myocardial infarction [67], heart failure [66,68], and atherosclerosis [69].
Oxidative stress alters ion channel function [21], impairs mitochondrial respiration [4], promotes lipid peroxidation [70], and triggers maladaptive remodeling through the activation of redox-sensitive transcription factors such as NF-κB and AP-1 [71]. These molecular disturbances are linked to the progression of heart failure, ischemia-reperfusion injury, atrial fibrillation, and hypertrophy [24,72]. Emerging evidence suggests that ROS within subcellular compartments, specifically mitochondria, are critical in determining cellular outcomes. Excessive mitochondrial ROS has been observed in cardiomyocytes from experimental models of myocardial infarction and rapid pacing-induced heart failure [73]. ROS can also react with nitric oxide (NO) to produce peroxynitrite (ONOO−), which lowers NO availability and disrupts both vascular and cardiac function, a process especially associated with hypertension and heart failure [73,74]. Therefore, understanding the specific redox alterations in cardiomyocytes is essential for identifying therapeutic targets aimed at restoring redox balance and preventing cardiac dysfunction. Figure 4 illustrates how oxidative stress contributes to cardiac damage and disease.

4. Redox-Dependent Regulation of Cardiac Ion Channels

Reactive oxygen species influence various signaling cascades in cardiomyocytes [13]. They do so by modifying thiol groups on key regulatory proteins, such as kinases, phosphatases, and transcription factors, that serve as secondary messengers for essential cellular functions [75,76]. Among these, protein kinase C (PKC) is particularly well characterized. In response to ROS, PKC in cardiac cells enhances L-type Ca2+ channel opening [77], phosphorylates and activates Na+ channels [78,79], and alters various K+ currents [80,81,82].
Intracellular redox balance exerts a profound modulatory effect on ion channel gating. Reactive oxygen and nitrogen species selectively modify pore-forming channel subunits: nitric oxide (•NO) S-nitrosylates critical cysteine thiols [83], peroxynitrite (ONOO−) nitrates tyrosine residues [84], and hydrogen peroxide (H2O2) oxidizes cysteine thiols to sulfenic (–SOH), sulfinic (–SO2H), and disulfide (–S–S–) forms [85], as illustrated in Figure 5 [86,87,88]. Functional studies under oxidative conditions have determined distinct biophysical changes in various ion channel families, linking these alterations to cardiac pathophysiological phenotypes (Table 2). This table presents key studies investigating the redox-dependent regulation of cardiac ion channels across diverse experimental models. From rat and mouse cardiomyocytes to heterologous expression systems, these results collectively determine how oxidative modifications, such as glutathionylation, sulfenic acid formation, S-nitrosylation, and disulfide cross-linking, alter the gating expression of potassium, calcium, and sodium channels. Such changes contribute to pathologies ranging from ischemia-reperfusion injury and diabetic cardiomyopathy to arrhythmias and heart failure. In the following section, we will review each redox-sensitive channel in more detail, studying their molecular modification sites, biophysical consequences, and therapeutic implications.

4.1. Redox-Sensitive Ion Channels in the Heart:

Redox-sensitive ion channels have emerged as key modulators of the cardiac action potential [103]. These channels respond dynamically to the cellular redox state as critical links between oxidative stress and alterations in cardiac electrophysiology [13]. Redox-sensitive ion channels significantly maintain cardiac rhythm and contractility under normal conditions by influencing cardiomyocytes’ ion flow and electrical signaling. However, under oxidative stress, their altered function can contribute to the development of arrhythmias and further exacerbate cardiac dysfunction [13,20]. ROS effects on various redox-sensitive cardiac ion channels are reviewed below.

4.1.1. Redox Regulation of Cardiac Potassium Channels

Cardiac K+ currents are classified by channel topology and distinct functional and pharmacological profiles [104]. Each channel contains four pore-forming α-subunits arranged around a central pore, together with regulatory β-subunits and associated proteins, such as kinases, phosphatases, or cytoskeletal elements, that regulate their gating and cellular localization [16,36]. With various K+ channel complexes and varied ROS effects, it is essential to determine ROS sites, whether on channel proteins, auxiliary subunits, or membrane lipids [105]. Acute ROS actions often target specific amino acids (Cys, Met, Tyr, and His), while broader shifts in redox couples (e.g., GSH/GSSG, NADPH/NADP+, Fe2+/Fe3+) can also modulate channel function. Voltage-gated (Kv) channels open upon depolarization and include the transient outward current Ito, the ultra-rapid IKur, rapid IKr, and slow IKS components of the delayed rectifier, as well as the inward rectifier IK1 [30,31]. KV channels are essential for several physiological processes, including muscle contraction, the regulation of resting membrane potential, the control of shape, the duration and frequency of action potentials, and secretion [86,106,107]. Prolonged oxidative stress induces sulfenic acid formation on KV1.5, reducing its surface expression, making KV1.5 sulfenylation a potential atrial fibrillation target [93]. Other redox-sensitive cardiac potassium channels include KATP channels, which close in response to intracellular ATP. They assemble from inward rectifier potassium channels (Kir) pore-forming subunits Kir6.1 or Kir6.2 and regulatory sulfonylurea receptor (SUR) proteins (SUR1, SUR2A, and SUR2B). Because they open when ATP levels fall, KATP channels sense cellular metabolism and oxygen availability, helping protect the heart during ischemia reperfusion by shortening action potentials, conserving energy, and stabilizing mitochondrial function [91,108]. Calcium-activated KCa channels are functionally coupled to Cav-mediated Ca2+ entry. Small KCa or SK activation lowers mitochondrial ROS and prevents cysteine oxidation on RyR2 [95]. Leak K+ channels conduct background currents independent of voltage or ligand binding. The transient outward current Ito is reversibly inhibited by oxidants (e.g., glutathione disulfide, diamide) through disulfide bond formation between key cysteines; reducing agents such as DTT restore Ito amplitude [13].

4.1.2. Redox Control of Cardiac Sodium Channels

Voltage-gated Na+ channels are also redox targets [97,98,109]. The oxidative modification of extracellular cysteines via disulfide exchange alters toxin and drug binding [86], whereas mitochondrial ROS produced by carbon monoxide donor carbon monoxide-releasing molecule-2 (CORM-2) oxidize intracellular methionine/cysteine residues in NaV1.5 to reduce peak current and slow inactivation [98]. Reducing agents such as DTT reverse these effects, whereas small-molecule NO-releasing compounds can modulate the late sodium current via S-nitrosylation [110], suggesting that targeted redox modulation may correct conduction defects in ischemia-related arrhythmias.

4.1.3. Redox Regulation of Cardiac Calcium Channels

Depolarization opens voltage-gated L-type Ca2+ channels in the sarcolemma, allowing a small Ca2+ influx that activates ryanodine receptors (RyRs) on the sarcoplasmic reticulum in a process called calcium-induced calcium release (CICR) [15]. Cytosolic Ca2+ is then cleared by the SERCA pump back into the SR and by the NCX exchanger out of the cell [111]. Reactive oxygen species modulate each of these components, altering overall cellular Ca2+ levels [100]. L-type Ca2+ channels exhibit complex redox regulation. S-nitrosothiols and SIN-1 enhance Cav1.2 open probability through S-nitrosylation of critical thiols, increasing ICa,L, and boosting contractility under mild oxidative stimuli [40,100]. In contrast, glutathionylation of Cav1.2, induced by oxidized glutathione in HEK293 expression systems, further potentiates calcium influx during sustained redox shifts, an effect reversible by glutaredoxin mimetics [14,102].

4.1.4. Redox Regulation of Other Ion Channels

Redox regulation significantly affects the function of various ion channels, including chloride channels, which are critical in cardiac physiology [112]. Chloride channels help set the resting membrane potential, shape action potentials, and control cell volume in the heart [113]. Chloride channels are known to respond to redox states, particularly through the modification of cysteine residues within their structure [86]. Mild oxidative environments can induce reversible modifications that enhance the activity of these channels, while excessive oxidative stress can lead to permanent inactivation [114]. Volume-regulated anion channels (VRACs) and Ca2+-activated Cl− channels (CaCCs) both sense intracellular redox shifts. VRAC activation under oxidative stress limits ischemia-induced swelling, while redox-dependent modulation of CaCCs influences excitability and arrhythmia risk [115]. Therefore, selective redox-modulating drugs, either thiol-protective antioxidants or targeted channel modulators, would offer promising strategies to correct chloride channel dysfunction in oxidative cardiac disease [116]. By restoring Cl− flux, these mediators could stabilize electrical activity, prevent cell swelling, and improve cardiac outcomes under stress.

5. Therapeutic Strategies Targeting Redox-Sensitive Ion Channels in Cardiac Disease

Redox-sensitive ion channels represent attractive druggable targets to improve oxidative cardiac injury. Small molecules that stabilize NaV1.5 by preventing cysteine oxidation have demonstrated anti-arrhythmic effects under oxidative stress [117]. Similarly, Kv channel modulators ranging from selective peptides to antioxidants such as N-acetylcysteine (NAC) effectively restore repolarization kinetics and suppress redox-driven arrhythmias [118]. NAC additionally substitutes for intracellular glutathione, blocking the disulfide cross-linking of channel thiols and reducing arrhythmia burden in ischemia-reperfusion models [119]. An alternative approach utilizes soluble guanylate cyclase (sGC) stimulators such as vericiguat to increase cGMP signaling, thereby conferring redox protection and vasodilation [120]. Vericiguat was found to inhibit hERG-mediated K+ tail currents in a concentration-dependent manner, without evidence of proarrhythmic risk in nonclinical in vitro and in vivo studies [121]. The increase in cGMP also activates PKG, which adds nitric oxide groups (S-nitrosylation) to hKv1.5 channels, reversing harmful thiol oxidation and reducing channel activity [122]. Emerging device-based interventions, notably, left bundle branch area pacing (LBBAP), may synergize with pharmacological redox therapies to reinforce electrical stability in heart failure with reduced ejection fraction (HFrEF) [123,124]. Despite these advances, two critical challenges must be overcome to enable clinical application. First, therapies must achieve cardiac-specific action: systemic delivery of broad-spectrum antioxidants or sGC stimulators risks the off-target modulation of vascular and neuronal ion channels, potentially precipitating hypotension or neurotoxicity [16,125]. Second, the dynamic redox environment of the myocardium and the narrow therapeutic window of ROS/RNS require innovations in targeted delivery and dose optimization [126]. Addressing these issues is key for the successful translation of redox-directed ion channel modulators into standard cardiac clinical practice. Figure 6 provides a conceptual framework that combines a view of how ROS generation, channel-specific redox modifications, and targeted therapies interrelate in oxidative cardiac disease.

6. Concluding Remarks

Redox-sensitive ion channels involve a significant network through which oxidative signals shape cardiac excitability and contractile function. Potassium channels respond to thiol-based modifications, adjusting repolarization and protecting against after-depolarizations. Sodium channels combine extracellular and mitochondrial redox signals, modulating conduction velocity and arrhythmia. Calcium channels link redox state to excitation contraction coupling, with balanced S-nitrosylation and glutathionylation preserving contractile strength while preventing diastolic Ca2+ leak. Collectively, these findings highlight the contrast of ROS as both physiological mediators and pathological triggers. Reversible redox modifications offer an excellent therapeutic strategy. Compounds that support endogenous reductive systems, selectively reverse harmful channel oxidation, or stimulate soluble guanylate cyclase to bolster cGMP-mediated redox balance hold promise for restoring electrical stability and contractile performance in oxidative cardiac disease. A deep understanding of channel-specific redox mechanisms is essential for the development of precision therapies that restore and sustain electrophysiological homeostasis in oxidative cardiac disease.

Author Contributions

Writing—original draft preparation, R.O., A.H.G.E.-D.; V.K., E.L. and V.X.; writing—review and editing, O.A., A.R. and A.A. (Abdullah Alwatban); visualization, M.Z., A.A. (Ali Alaseem) and Y.-W.N. supervision. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported and funded by the Deanship of Scientific Research at Imam Mohammad ibn Saud Islamic University (IMSIU) (grant number IMSIU-DDRSP2501).

Data Availability Statement

Data sharing is not applicable.

Acknowledgments

Figures are created with BioRender (https://www.biorender.com/) and published with permission. M.Z. was supported by American Heart Association (Grant 23AIREA1039423) and Chapman University Institutional FGRSC Grant. Y.W.N was supported by American Heart Association (24CDA1260237).

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

APAction Potential
Ca2+Calcium Ion
CICRCalcium-Induced Calcium Release
DTTDithiothreitol
ECCExcitation–Contraction Coupling
GSSGGlutathione Disulfide
H2O2Hydrogen Peroxide
IFFunny Current (Pacemaker “If” Current)
INaFast Sodium Current
ICa,LL-Type Calcium Current
ICa,TT-Type Calcium Current
IK1Inward Rectifier Potassium Current
IKrRapid Delayed Rectifier Potassium Current
IKsSlow Delayed Rectifier Potassium Current
IKurUltrarapid Delayed Rectifier Potassium Current
ItoTransient Outward Potassium Current
ROSReactive Oxygen Species
RyR2Ryanodine Receptor Type 2
SASinoatrial (Node)
SCDSudden Cardiac Death
SRSarcoplasmic Reticulum
SERCASarco/Endoplasmic Reticulum Ca2+-ATPase
TRPC6Transient Receptor Potential Canonical 6

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Figure 1. Simplified ventricular myocyte showing action-potential phases and ion channel localization. Connexin43-based gap junctions, Igi (green) at intercellular borders, conduct rapid ionic currents between adjacent myocytes, triggering Phase 0 depolarization. This activation opens fast inward currents (red), primarily INa and ICa,T, which inactivate quickly, while L-type Ca2+ channels (ICa,L) remain active longer to sustain the plateau (Phase 2). The depolarizing influence of ICa,L is then opposed by early outward K+ currents (Ito, blue), and by ultrarapid/delayed rectifier currents (IKur, IKr, IKs), which drive repolarization. Finally, inward rectifier K+ current (IK1, dark blue) restores the membrane to its resting potential (approximately −85 mV) [25]. Phase numbers (0–4) are marked along the voltage trace.
Figure 1. Simplified ventricular myocyte showing action-potential phases and ion channel localization. Connexin43-based gap junctions, Igi (green) at intercellular borders, conduct rapid ionic currents between adjacent myocytes, triggering Phase 0 depolarization. This activation opens fast inward currents (red), primarily INa and ICa,T, which inactivate quickly, while L-type Ca2+ channels (ICa,L) remain active longer to sustain the plateau (Phase 2). The depolarizing influence of ICa,L is then opposed by early outward K+ currents (Ito, blue), and by ultrarapid/delayed rectifier currents (IKur, IKr, IKs), which drive repolarization. Finally, inward rectifier K+ current (IK1, dark blue) restores the membrane to its resting potential (approximately −85 mV) [25]. Phase numbers (0–4) are marked along the voltage trace.
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Figure 2. Primary pathways of reactive oxygen species (ROS) generation in cardiomyocytes. Within mitochondria, a small portion of electrons “leaks” from complexes I, II, and III onto O2, forming the superoxide anion (O2·−). Superoxide also arises in the cytosol when NADPH oxidase transfers electrons from NADPH to O2 and when xanthine oxidase oxidizes hypoxanthine to xanthine. Mitochondrial O2·− diffuses into the cytosol, where it can convert hydrogen peroxide (H2O2) into hydroxyl radicals (·OH) via the Haber–Weiss reaction. Peroxisomes generate much of the cell’s H2O2, but if peroxisomal defenses fail, H2O2 spills into the cytosol, fueling further ·OH production. Under metabolic stress, iron released from 4Fe_4S enzyme clusters drives the Fenton reaction, producing additional ·OH from H2O2. Lipid peroxidation creates membrane peroxyl radicals (ROO·), while excessive nitric oxide (·NO), formed by nitric oxide synthase, combines with O2·− to yield the potent oxidant peroxynitrite (ONOO−), contributing to nitrosative stress [13].
Figure 2. Primary pathways of reactive oxygen species (ROS) generation in cardiomyocytes. Within mitochondria, a small portion of electrons “leaks” from complexes I, II, and III onto O2, forming the superoxide anion (O2·−). Superoxide also arises in the cytosol when NADPH oxidase transfers electrons from NADPH to O2 and when xanthine oxidase oxidizes hypoxanthine to xanthine. Mitochondrial O2·− diffuses into the cytosol, where it can convert hydrogen peroxide (H2O2) into hydroxyl radicals (·OH) via the Haber–Weiss reaction. Peroxisomes generate much of the cell’s H2O2, but if peroxisomal defenses fail, H2O2 spills into the cytosol, fueling further ·OH production. Under metabolic stress, iron released from 4Fe_4S enzyme clusters drives the Fenton reaction, producing additional ·OH from H2O2. Lipid peroxidation creates membrane peroxyl radicals (ROO·), while excessive nitric oxide (·NO), formed by nitric oxide synthase, combines with O2·− to yield the potent oxidant peroxynitrite (ONOO−), contributing to nitrosative stress [13].
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Figure 3. Antioxidant systems in cardiomyocytes. Key antioxidants include reduced glutathione (GSH) and its oxidized form (GSSG), supported by antioxidant enzymes such as glutathione reductase (GRed), glutathione peroxidase (GPx), catalase, and superoxide dismutase (SOD). Additional components include NADPH oxidase, α-tocopherol (vitamin E), and vitamin C. Abbreviations: (RCOO•) lipid radical; (RCOOH) lipid; (α-toco•) α-tocopheroxyl radical; (α-toco) α-tocopherol.
Figure 3. Antioxidant systems in cardiomyocytes. Key antioxidants include reduced glutathione (GSH) and its oxidized form (GSSG), supported by antioxidant enzymes such as glutathione reductase (GRed), glutathione peroxidase (GPx), catalase, and superoxide dismutase (SOD). Additional components include NADPH oxidase, α-tocopherol (vitamin E), and vitamin C. Abbreviations: (RCOO•) lipid radical; (RCOOH) lipid; (α-toco•) α-tocopheroxyl radical; (α-toco) α-tocopherol.
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Figure 4. The impact of oxidative stress on heart diseases. An imbalance between ROS and antioxidants shifts redox signaling toward oxidative stress, contributing to heart failure, hypertension, and atherosclerosis, often resulting in irreversible cardiac damage. ROS, reactive oxygen species; NO, nitric oxide [73].
Figure 4. The impact of oxidative stress on heart diseases. An imbalance between ROS and antioxidants shifts redox signaling toward oxidative stress, contributing to heart failure, hypertension, and atherosclerosis, often resulting in irreversible cardiac damage. ROS, reactive oxygen species; NO, nitric oxide [73].
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Figure 5. Redox-dependent modulation of a cardiac ion channel gating. Reactive oxygen species (ROS) oxidize critical cysteine thiols (orange) on the voltage-sensing domain of the voltage-gated channel, converting them into sulfenic and disulfide forms (green). In the left panel, ROS (red burst) targets the resting channel, initiating thiol oxidation and a partial opening state. These oxidative modifications shift the activation threshold and increase open probability, as depicted on the right by more frequent and longer-lasting ion flux (dense blue dots). Under reducing conditions, thiol groups are restored, and normal gating is recovered.
Figure 5. Redox-dependent modulation of a cardiac ion channel gating. Reactive oxygen species (ROS) oxidize critical cysteine thiols (orange) on the voltage-sensing domain of the voltage-gated channel, converting them into sulfenic and disulfide forms (green). In the left panel, ROS (red burst) targets the resting channel, initiating thiol oxidation and a partial opening state. These oxidative modifications shift the activation threshold and increase open probability, as depicted on the right by more frequent and longer-lasting ion flux (dense blue dots). Under reducing conditions, thiol groups are restored, and normal gating is recovered.
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Figure 6. Diagram of redox-dependent modulation of cardiac ion channels and therapeutic interventions. Mitochondrial electron-transport chain leakage, NADPH oxidases, and xanthine oxidase generate reactive oxygen species (ROS: O2•−, H2O2, •OH), which impart redox modifications (e.g., S-nitrosylation, glutathionylation, disulfide formation) on voltage-gated Na+, Ca2+, and K+ channels. These thiol-based modifications alter channel gating, leading to disrupted excitability and contractility in ventricular myocytes. Targeted therapeutic strategies, including antioxidants that boost endogenous reductive systems, soluble guanylate cyclase (sGC) stimulators that enhance cGMP-PKG–mediated thiol protection, and device-based pacing (e.g., LBBAP), aim to reverse maladaptive channel oxidation, restore electrical stability, and improve contractile function in oxidative cardiac disease.
Figure 6. Diagram of redox-dependent modulation of cardiac ion channels and therapeutic interventions. Mitochondrial electron-transport chain leakage, NADPH oxidases, and xanthine oxidase generate reactive oxygen species (ROS: O2•−, H2O2, •OH), which impart redox modifications (e.g., S-nitrosylation, glutathionylation, disulfide formation) on voltage-gated Na+, Ca2+, and K+ channels. These thiol-based modifications alter channel gating, leading to disrupted excitability and contractility in ventricular myocytes. Targeted therapeutic strategies, including antioxidants that boost endogenous reductive systems, soluble guanylate cyclase (sGC) stimulators that enhance cGMP-PKG–mediated thiol protection, and device-based pacing (e.g., LBBAP), aim to reverse maladaptive channel oxidation, restore electrical stability, and improve contractile function in oxidative cardiac disease.
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Table 2. Summary of key studies on redox modulation of cardiac ion channels under oxidative stress. * Indicates clinically relevant, in vivo or translational studies.
Table 2. Summary of key studies on redox modulation of cardiac ion channels under oxidative stress. * Indicates clinically relevant, in vivo or translational studies.
Channel TypeSpeciesExperimental DesignChannel/SubtypeRedox ModificationRelated DiseaseEffect on Ion ChannelReference
K+ channelsRatsPatch clamp electrophysiologyTransient outward potassium current (Ito)Oxidized glutathione (GSSG), 5,5-dithiobis-(2-nitrobenzoic acid)Ischemia and reperfusion *Oxidative stress decreases Ito amplitude, reversible by reducing agents[89]
RatsAnimal model; spectrophotometric assays; patch clamp electrophysiologyTransient outward potassium current (Ito)Thioredoxin and glutaredoxin systemsDiabetic cardiomyopathy *Diabetes alters redox systems, affecting K+ channel remodeling[90]
Rat ventricular myocytesPatch clamp; GSSG/H2O2 vs. GSH/DTTKATPGSSG/H2O2 activates IKATP reversed by GSH/DTTIschemia-reperfusion injuryActivation via PKC, PKG, CaMKII[91]
RatsAnimal model and in vitro, patch clamp electrophysiology(Ipeak and Iss)Diamide, thioredoxin, and glutaredoxin systems__Oxidative stress decreases K+ currents, regulated by redox systems[92]
Mouse ventricular myocytesIn vitro cellular study; patch clamp electrophysiology; Western blottingKv1.5 (KCNA5)Sulfenic acid modificationAtrial fibrillation and hypoxic pulmonary hypertensionSulfenic acid modification of Kv1.5 reduces channel surface expression[93]
HEK293 cellsPatch clamp with DTT/GSSGKv1.2Disulfide bond togglingArrhythmiaRedox shifts activation voltage[94]
RatEx vivo hypertrophic hearts; myocyte patch clamp; mito ROSSK channels (Small conductance Ca2-activated K+ channels)Prevents RyR2 cysteine oxidationHeart failure/hypertrophySK activation lowers mitochondrial ROS and prevents cysteine oxidation on RyR2[95]
HEK293 cellsInside-out patch + H2O2BK/Slo1 (Big conductance Ca2+activated K+ channels)Cysteine oxidationHypertensionROS inhibit BK via Ca2+-sensing cysteines[96]
Na+ channelsXenopus oocytesTwo-electrode voltage clamp with μO§-conotoxinVoltage-gated Na+ channel (NaV1.2/1.6)Disulfide bond formation at Cys910Arrhythmia model *Cys910 redox state controls channel–toxin binding[97]
HEK293 cells (human Nav1.5)Heterologous expression; whole-cell patch clamp; CO donor (CORM-2) application; mitochondrial ROS assaysVoltage-gated Na+ channel (NaV1.5)Mitochondrial ROS-mediated cysteine oxidationIschemia-related arrhythmias *Carbon monoxide triggers mitochondrial ROS that oxidize Nav1.5 cysteines, reducing peak Na+ current[98]
MouseAng II infusion; BP telemetry; ROS assayENaC (epithelial Na+ channel)NOX1-derived ROS ↑HypertensionNoxa1 deletion reduces ENaC activation[99]
Ca2+ channelsFerretPatch clamp electrophysiologyL-type calcium channelSIN-1 (NO and O2− donor); S-nitrosothiols__NO and S-nitrosothiols modulate L-type Ca2+ channel activity[100]
MouseTRPC6 knockout vs. mice; transverse aortic constriction; ROS assaysTRPC6 (Transient Receptor Potential Canonical 6)Disrupts TRPC3–Nox2, lowers ROSDiabetic heart failureTRPC6 limits ROS, preserves function[101]
HEK293 cellsProteoliposome experiments; patch clamp electrophysiologyL-type calcium channel (Cav1.2)Thiol-modifying agents (DTT, DTNB)IschemiaOxidative stress modifies Cav1.2 open probability via specific cysteine residues[102]
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Orfali, R.; Gamal El-Din, A.H.; Karthick, V.; Lamis, E.; Xiao, V.; Ramanishka, A.; Alwatban, A.; Alkhamees, O.; Alaseem, A.; Nam, Y.-W.; et al. Modulation of Redox-Sensitive Cardiac Ion Channels. Antioxidants 2025, 14, 836. https://doi.org/10.3390/antiox14070836

AMA Style

Orfali R, Gamal El-Din AH, Karthick V, Lamis E, Xiao V, Ramanishka A, Alwatban A, Alkhamees O, Alaseem A, Nam Y-W, et al. Modulation of Redox-Sensitive Cardiac Ion Channels. Antioxidants. 2025; 14(7):836. https://doi.org/10.3390/antiox14070836

Chicago/Turabian Style

Orfali, Razan, Al Hassan Gamal El-Din, Varnika Karthick, Elisanjer Lamis, Vanna Xiao, Alena Ramanishka, Abdullah Alwatban, Osama Alkhamees, Ali Alaseem, Young-Woo Nam, and et al. 2025. "Modulation of Redox-Sensitive Cardiac Ion Channels" Antioxidants 14, no. 7: 836. https://doi.org/10.3390/antiox14070836

APA Style

Orfali, R., Gamal El-Din, A. H., Karthick, V., Lamis, E., Xiao, V., Ramanishka, A., Alwatban, A., Alkhamees, O., Alaseem, A., Nam, Y.-W., & Zhang, M. (2025). Modulation of Redox-Sensitive Cardiac Ion Channels. Antioxidants, 14(7), 836. https://doi.org/10.3390/antiox14070836

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