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Delayed rectifier K+ current (IKs) is a key contributor to repolarization of action potentials. This study investigated the mechanisms underlying the adrenoceptor-induced potentiation of IKs in pulmonary vein cardiomyocytes (PVC). PVC were isolated from guinea pig pulmonary vein. The action potentials and IKs current were recorded using perforated and conventional whole-cell patch-clamp techniques. The expression of IKs was examined using immunocytochemistry and Western blotting. KCNQ1, a IKs pore-forming protein was detected as a signal band approximately 100 kDa in size, and its immunofluorescence signal was found to be mainly localized on the cell membrane. The IKs current in PVC was markedly enhanced by both β1- and β2-adrenoceptor stimulation with a negative voltage shift in the current activation, although the potentiation was more effectively induced by β2-adrenoceptor stimulation than β1-adrenoceptor stimulation. Both β-adrenoceptor-mediated increases in IKs were attenuated by treatment with the adenylyl cyclase (AC) inhibitor or protein kinase A (PKA) inhibitor. Furthermore, the IKs current was increased by α1-adrenoceptor agonist but attenuated by the protein kinase C (PKC) inhibitor. PVC exhibited action potentials in normal Tyrode solution which was slightly reduced by HMR-1556 a selective IKs blocker. However, HMR-1556 markedly reduced the β-adrenoceptor-potentiated firing rate. The stimulatory effects of β- and α1-adrenoceptor on IKs in PVC are mediated via the PKA and PKC signal pathways. HMR-1556 effectively reduced the firing rate under β-adrenoceptor activation, suggesting that the functional role of IKs might increase during sympathetic excitation under in vivo conditions.

DOI： 10.1016/j.yjmcc.2021.08.004

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The atrioventricular (AV) node is the only conduction pathway where electrical impulse can pass from atria to ventricles and exhibits spontaneous automaticity. This study examined the function of the rapid- and slow-activating delayed rectifier K+ currents (IKr and IKs) in the regulation of AV node automaticity. Isolated AV node cells from guinea pigs were current- and voltage-clamped to record the action potentials and the IKr and IKs current. The expression of IKr or IKs was confirmed in the AV node cells by immunocytochemistry, and the positive signals of both channels were localized mainly on the cell membrane. The basal spontaneous automaticity was equally reduced by E4031 and HMR-1556, selective blockers of IKr and IKs, respectively. The nonselective β-adrenoceptor agonist isoproterenol markedly increased the firing rate of action potentials. In the presence of isoproterenol, the firing rate of action potentials was more effectively reduced by the IKs inhibitor HMR-1556 than by the IKr inhibitor E4031. Both E4031 and HMR-1556 prolonged the action potential duration and depolarized the maximum diastolic potential under basal and β-adrenoceptor-stimulated conditions. IKr was not significantly influenced by β-adrenoceptor stimulation, but IKs was concentration-dependently enhanced by isoproterenol (EC50: 15 nM), with a significant negative voltage shift in the channel activation. These findings suggest that both the IKr and IKs channels might exert similar effects on regulating the repolarization process of AV node action potentials under basal conditions; however, when the β-adrenoceptor is activated, IKs modulation may become more important.

DOI： 10.1007/s00424-021-02617-z

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BACKGROUND AND PURPOSE: The slowly activating delayed rectifier K+ channel (IKs ), composed of pore-forming KCNQ1 α-subunits and ancillary KCNE1 β-subunits, regulates ventricular repolarization in human heart. Propofol, at clinically used concentrations, modestly inhibits the intact (wild-type) IKs channels and is therefore unlikely to appreciably prolong QT interval in ECG during anaesthesia. However, little information is available concerning the inhibitory effect of propofol on IKs channel associated with its gene variants implicated in QT prolongation. The KCNE1 single nucleotide polymorphism leading to D85N is associated with drug-induced QT prolongation and therefore regarded as a clinically important genetic variant. This study examined whether KCNE1-D85N affects the sensitivity of IKs to inhibition by propofol. EXPERIMENTAL APPROACH: Whole-cell patch-clamp and immunostaining experiments were conducted in HEK293 cells and/or mouse cardiomyocyte-derived HL-1 cells, transfected with wild-type KCNQ1, wild-type or variant KCNE1 cDNAs. KEY RESULTS: Propofol inhibited KCNQ1/KCNE1-D85N current more potently than KCNQ1/KCNE1 current in HEK293 cells and HL-1 cells. Immunostaining experiments in HEK293 cells revealed that pretreatment with propofol (10 μM) did not appreciably affect cell membrane expression of KCNQ1 and KCNE1 proteins in KCNQ1/KCNE1 and KCNQ1/KCNE1-D85N channels. CONCLUSION AND IMPLICATIONS: The KCNE1 polymorphism D85N significantly elevates the sensitivity of IKs to inhibition by propofol. This study detects a functionally important role of KCNE1-D85N polymorphism in conferring genetic susceptibility to propofol-induced QT prolongation and further suggests the possibility that the inhibitory action of anaesthetics on ionic currents becomes exaggerated in patients carrying variants in genes encoding ion channels.

DOI： 10.1111/bph.15460

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In basic research using mouse heart, isolating viable individual cardiomyocytes is a crucial technical step to overcome. Traditionally, isolating cardiomyocytes from rabbits, guinea pigs or rats has been performed via retrograde perfusion of the heart with enzymes using a Langendorff apparatus. However, a high degree of skill is required when this method is used with a small mouse heart. An antegrade perfusion method that does not use a Langendorff apparatus was recently reported for the isolation of mouse cardiomyocytes. We herein report a complete protocol for the improved antegrade perfusion of the excised heart to isolate individual heart cells from adult mice (8 - 108 weeks old). Antegrade perfusion is performed by injecting perfusate near the apex of the left ventricle of the excised heart, the aorta of which was clamped, using an infusion pump. All procedures are carried out on a pre-warmed heater mat under a microscope, which allows for the injection and perfusion processes to be monitored. The results suggest that ventricular and atrial myocytes, and fibroblasts can be well isolated from a single adult mouse simultaneously.

DOI： 10.3791/61866

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DOI： 10.3389/fcell.2021.597997

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BACKGROUND AND PURPOSE: Volatile anaesthetics have been shown to differentially modulate mammalian Shaker-related voltage-gated potassium (Kv 1.x) channels. This study was designed to investigate molecular and cellular mechanisms underlying the modulatory effects of desflurane or sevoflurane on human Kv 1.5 (hKv 1.5) channels. EXPERIMENTAL APPROACH: Thirteen single-point mutations were constructed within pore domain of hKv 1.5 channel using site-directed mutagenesis. The effects of desflurane or sevoflurane on heterologously expressed wild-type and mutant hKv 1.5 channels were examined by whole-cell patch-clamp technique. A computer simulation was conducted to predict the docking pose of desflurane or sevoflurane within hKv 1.5 channel. KEY RESULTS: Both desflurane and sevoflurane increased hKv 1.5 current at mild depolarizations but decreased it at strong depolarizations, indicating that these anaesthetics produce both stimulatory and inhibitory actions on hKv 1.5 channels. The inhibitory effect of desflurane or sevoflurane on hKv 1.5 channels arose primarily from its open-channel blocking action. The inhibitory action of desflurane or sevoflurane on hKv 1.5 channels was significantly attenuated in T480A, V505A, and I508A mutant channels, compared with wild-type channel. Computational docking simulation predicted that desflurane or sevoflurane resides within the inner cavity of channel pore and has contact with Thr479, Thr480, Val505, and Ile508. CONCLUSION AND IMPLICATIONS: Desflurane and sevoflurane exert an open-channel blocking action on hKv 1.5 channels by functionally interacting with specific amino acids located within the channel pore. This study thus identifies a novel molecular basis mediating inhibitory modulation of hKv 1.5 channels by desflurane and sevoflurane.

DOI： 10.1111/bph.15105

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DOI： 10.3390/cells14030216

PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

The atrophic myocardium resulting from mechanical unloading and nutritional deprivation is considered crucial as maladaptive remodeling directly associated with heart failure, as well as interstitial fibrosis. Conversely, myocardial hypertrophy resulting from hemodynamic loading is perceived as compensatory stress adaptation. We previously reported the abundant presence of highly redox-active polysulfide molecules, termed supersulfide, with two or more sulfur atoms catenated in normal hearts, and the supersulfide catabolism in pathologic hearts after myocardial infarction correlated with worsened prognosis of heart failure. However, the impact of supersulfide on myocardial remodeling remains unclear. Here, we investigated the involvement of supersulfide metabolism in cardiomyocyte remodeling, using a model of adenosine 5′-triphosphate (ATP) receptor-stimulated atrophy and endothelin-1 receptor-stimulated hypertrophy in neonatal rat cardiomyocytes. Results revealed contrasting changes in intracellular supersulfide and its catabolite, hydrogen sulfide (H2S), between cardiomyocyte atrophy and hypertrophy. Stimulation of cardiomyocytes with ATP decreased supersulfide activity, while H2S accumulation itself did not affect cardiomyocyte atrophy. This supersulfide catabolism was also involved in myofibroblast formation of neonatal rat cardiac fibroblasts. Thus, unraveling supersulfide metabolism during myocardial remodeling may lead to the development of novel therapeutic strategies to improve heart failure.

DOI： 10.1016/j.jphs.2024.05.002

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Language：English   Publisher：British Journal of Pharmacology  

Background and purpose: Maintaining mitochondrial quality is attracting attention as a new strategy to treat diabetes and diabetic complications. We previously reported that mitochondrial hyperfission by forming a protein complex between dynamin-related protein (Drp) 1 and filamin, mediates chronic heart failure and cilnidipine, initially developed as an L/N-type Ca2+ channel blocker, improves heart failure by inhibiting Drp1-filamin protein complex. We investigated whether cilnidipine improves hyperglycaemia of various diabetic mice models. Experimental Approach: Retrospective analysis focusing on haemoglobin A1c (HbA1c) was performed in hypertensive and hyperglycaemic patients taking cilnidipine and amlodipine. After developing diabetic mice by streptozotocin (STZ) treatment, an osmotic pump including drug was implanted intraperitoneally, followed by weekly measurements of blood glucose levels. Mitochondrial morphology was analysed by electron microscopy. A Ca2+ channel-insensitive cilnidipine derivative (1,4-dihydropyridine [DHP]) was synthesized and its pharmacological effect was evaluated using obese (ob/ob) mice fed with high-fat diet (HFD). Key Results: In patients, cilnidipine was superior to amlodipine in HbA1c lowering effect. Cilnidipine treatment improved systemic hyperglycaemia and mitochondrial morphological abnormalities in STZ-exposed mice, without lowering blood pressure. Cilnidipine failed to improve hyperglycaemia of ob/ob mice, with suppressing insulin secretion. 1,4-DHP improved hyperglycaemia and mitochondria abnormality in ob/ob mice fed HFD. 1,4-DHP and cilnidipine improved basal oxygen consumption rate of HepG2 cells cultured under 25 mM glucose. Conclusion and implications: Inhibition of Drp1-filamin protein complex formation becomes a new strategy for type 2 diabetes treatment.

DOI： 10.1111/bph.16487

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：International Journal of Molecular Sciences  

Lipid droplet (LD) accumulation in hepatocytes is one of the major symptoms associated with fatty liver disease. Mitochondria play a key role in catabolizing fatty acids for energy production through β-oxidation. The interplay between mitochondria and LD assumes a crucial role in lipid metabolism, while it is obscure how mitochondrial morphology affects systemic lipid metabolism in the liver. We previously reported that cilnidipine, an already existing anti-hypertensive drug, can prevent pathological mitochondrial fission by inhibiting protein-protein interaction between dynamin-related protein 1 (Drp1) and filamin, an actin-binding protein. Here, we found that cilnidipine and its new dihydropyridine (DHP) derivative, 1,4-DHP, which lacks Ca2+ channel-blocking action of cilnidipine, prevent the palmitic acid-induced Drp1-filamin interaction, LD accumulation and cytotoxicity of human hepatic HepG2 cells. Cilnidipine and 1,4-DHP also suppressed the LD accumulation accompanied by reducing mitochondrial contact with LD in obese model and high-fat diet-fed mouse livers. These results propose that targeting the Drp1-filamin interaction become a new strategy for the prevention or treatment of fatty liver disease.

DOI： 10.3390/ijms25105446

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Biochemistry  

Morphological and structural remodeling of the heart, including cardiac hypertrophy and fibrosis, has been considered as a therapeutic target for heart failure for approximately three decades. Groundbreaking heart failure medications demonstrating reverse remodeling effects have contributed significantly to medical advancements. However, nearly 50% of heart failure patients still exhibit drug resistance, posing a challenge to the healthcare system. Recently, characteristics of heart failure resistant to ARBs and β-blockers have been defined, highlighting preserved systolic function despite impaired diastolic function, leading to the classification of heart failure with preserved ejection fraction (HFpEF). The pathogenesis and aetiology of HFpEF may be related to metabolic abnormalities, as evidenced by its mimicry through endothelial dysfunction and excessive intake of high-fat diets. Our recent findings indicate a significant involvement of mitochondrial hyper-fission in the progression of heart failure. This mitochondrial pathological remodeling is associated with redox imbalance, especially hydrogen sulphide accumulation due to abnormal electron leak in myocardium. In this review, we also introduce a novel therapeutic strategy for heart failure from the current perspective of mitochondrial redox-metabolic remodeling.

DOI： 10.1093/jb/mvae031

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DOI： DOI: 10.3390/ijms25042401

Language：English   Publishing type：Research paper (scientific journal)   Publisher：International Journal of Molecular Sciences  

We recently reported that transient receptor potential canonical (TRPC) 6 channel activity contributes to intracellular Zn2+ homeostasis in the heart. Zn2+ has also been implicated in the regulation of intestinal redox and microbial homeostasis. This study aims to investigate the role of TRPC6-mediated Zn2+ influx in the stress resistance of the intestine. The expression profile of TRPC1-C7 mRNAs in the actively inflamed mucosa from inflammatory bowel disease (IBD) patients was analyzed using the GEO database. Systemic TRPC3 knockout (KO) and TRPC6 KO mice were treated with dextran sulfate sodium (DSS) to induce colitis. The Zn2+ concentration and the mRNA expression levels of oxidative/inflammatory markers in colon tissues were quantitatively analyzed, and gut microbiota profiles were compared. TRPC6 mRNA expression level was increased in IBD patients and DSS-treated mouse colon tissues. DSS-treated TRPC6 KO mice, but not TRPC3 KO mice, showed severe weight loss and increased disease activity index compared with DSS-treated WT mice. The mRNA abundances of antioxidant proteins were basically increased in the TRPC6 KO colon, with changes in gut microbiota profiles. Treatment with TRPC6 activator prevented the DSS-induced colitis progression accompanied by increasing Zn2+ concentration. We suggest that TRPC6-mediated Zn2+ influx activity plays a key role in stress resistance against IBD, providing a new strategy for treating colitis.

DOI： 10.3390/ijms25042401

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Language：English   Publisher：(公社)日本薬理学会  

ラット新生仔の心筋細胞にタバコ煙抽出物(CSE)を曝露すると、ミトコンドリア(MT)過剰分裂を介して心筋細胞老化が誘発された。CSEはMT分裂因子Drp1とアクチン結合蛋白質であるフィラミンA(FIL-A)との複合体形成を介して、MT分裂と活性酸素種(ROS)産生を引き起こした。シルニジピンやDrp1またはFIL-Aの遺伝子ノックダウンによりDrp1とFIL-Aの相互作用が変化し、CSE誘発性MT過剰分裂とROS産生、および心筋細胞老化を阻害した。Drp1活性の中心である酸化還元感受性をもったCys644について、CSEを介したFIL-Aとの相互作用において重要な役割を果たしていた。超硫黄分子(SS)供与体Na2S3の投与により、CSE誘発性MT過剰分裂を介して心筋細胞老化を改善した。以上より、Drp1-FIL-A複合体形成がタバコ煙介在性心リスクにおいて重要な役割を果たしており、MT分裂関連心筋細胞老化に対するSSの寄与が考えられた。

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

Smoking is one of the most serious risk factors for cardiovascular diseases. Although cigarette mainstream and sidestream smoke are significant contributors to increased cardiovascular mortality and morbidity, the underlying mechanism is still unclear. Here, we report that exposure of rat neonatal cardiomyocytes to cigarette smoke extract (CSE) induces mitochondrial hyperfission-mediated myocardial senescence. CSE leads to mitochondrial fission and reactive oxygen species (ROS) production through the complex formation between mitochondrial fission factor Drp1 and actin-binding protein, filamin A. Pharmacological perturbation of interaction between Drp1 and filamin A by cilnidipine and gene knockdown of Drp1 or filamin A inhibited CSE-induced mitochondrial hyperfission and ROS production as well as myocardial senescence. We previously reported that Drp1 activity is controlled by supersulfide-induced Cys644 polysulfidation. The redox-sensitive Cys644 was critical for CSE-mediated interaction with filamin A. The administration of supersulfide donor, Na2S3 also improved mitochondrial hyperfission-mediated myocardial senescence induced by CSE. Our results suggest the important role of Drp1-filamin A complex formation on cigarette smoke-mediated cardiac risk and the contribution of supersulfide to mitochondrial fission-associated myocardial senescence.

DOI： 10.1016/j.jphs.2023.12.008

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Language：Japanese   Publisher：The Japanese Society of Toxicology  

<p>Cardiac remodeling involves compensatory alterations in heart mass, geometry, and function in response to hemodynamic stress or cardiac injury. Previous studies have attributed myocardial variations to the size of cardiomyocytes. Recently, supersulfide, a sulfur-catenated molecule, has emerged as a crucial regulator of cardiac robustness. Our earlier findings revealed a heightened presence of supersulfide in healthy mouse hearts, which undergoes catabolism to hydrogen sulfide (H2S) following myocardial infarction. Despite these observations, the precise role of supersulfide metabolism in governing cardiac cellular functions remains elusive. In this study, we use cardiomyocytes isolated from ventricular of neonatal rat cardiomyocytes (NRCMs). We found that supersulfide, but not H2S, positively regulates the size of cardiomyocytes. qPCR results elucidated supersulfide anabolism related gene, Solute carrier family 7 member 11 (Slc7A11), may have involved in regulating size of cardiomyocytes. Slc7A11 gene knockdown efficiently induced cardiomyocyte atrophy. These findings suggest that supersulfide plays a key role in regulating cardiac cell remodeling induced by receptor stimulation. The anabolism and catabolism of supersulfide in cardiac cells could provide a new strategy for the treatment of pathological cardiac remodeling.</p>

DOI： 10.14869/toxpt.51.1.0_p-12s

CiNii Research

Language：Japanese   Publisher：The Japanese Society of Toxicology  

<p>Striated muscles, including cardiac muscle and red skeletal muscle which abundantly express myoglobin, play a crucial role not only in systemic motor function but also in the homeostasis of energy metabolism. The muscle atrophy that comes with age and disease will reduce systemic function. We have previously shown that the onset and progression of myocardial atrophy induced by the anticancer drug doxorubicin are mediated through the functional interactions between transient receptor potential canonical (TRPC) 3 protein and the ROS-producing NADPH oxidase 2 (Nox2), which is responsible for ROS production, on the cardiac myocyte membrane. We also identified ibudilast, a bronchodilator, can inhibit TRPC3-Nox2 complex formation and reduced the systemic muscle weight loss induced by doxorubicin. In this study, we investigated whether TRPC3/Nox2 complex formation is a therapeutic target for skeletal muscle atrophy in muscular dystrophy. In the skeletal muscle of Duchenne muscular dystrophy (mdx) model mice, TRPC3-Nox2 protein complex formation was markedly observed, and pharmacological inhibition of this complex formation by ibudilast attenuated skeletal muscle atrophy and motor functional loss in mdx mice. Furthermore, administration of pyrazole-3 (Pyr3), a TRPC3-selective inhibitor, to mdx mice similarly attenuated muscle atrophy and weakness. Oxidative stress caused in atrophied muscle cells was also suppressed by preventing TRPC3-Nox2 interaction. These results suggest that TRPC3-Nox2 complex formation may be a new therapeutic target for preventing myopathic muscle atrophy.</p>

DOI： 10.14869/toxpt.51.1.0_p-5s

CiNii Research

Language：Japanese   Publisher：The Japanese Society of Toxicology  

<p>The robustness of cardiomyocytes is supported by their superior redox homeostasis, and disruption of redox homeostasis leads to the onset and progression of cardiac disease. Supersulfides, which include catenated sulfur atoms (R-S_nSH) such as cysteine persulfide (Cys-SSH), have been recently identified as highly reactive sulfur metabolites and recognized as a key molecule to regulate redox homeostasis. This study aimed to elucidate the role of sulfur metabolism in maintaining cardiac robustness, and the impact of abnormal sulfur metabolism on ischemic and electrophilic stress-mediated cardiac dysfunction.</p><p>Supersulfides are reduced to hydrogen sulfides in cardiomyocytes after ischemic and electrophilic stress. This supersulfide catabolism decreased the contractile function of cardiomyocytes through mitochondrial hyperfission. We also found that the depletion of supersulfides promotes mitochondrial fission by decreasing polysulfidation of mitochondrial fission factor Drp1 at Cys644.</p><p>Our results suggest that the redox modification of Drp1 Cys644 has a pivotal role in the ischemic and electrophilic tolerance of cardiomyocytes. We found that this polysulfidated Cys644 is modified by S-glutathionylation. Drp1 was glutathionylated by oxidized GSSG but not reduced GSH. GSSG-mediated Drp1 glutathionylation protected cardiac function against ischemic and electrophilic stress in vitro and in vivo. These results suggest that sulfur metabolism has a pivotal role in ischemic and electrophilic stress-mediated cardiac dysfunction through Drp1 Cys644 redox modification.</p>

DOI： 10.14869/toxpt.51.1.0_s2-2

CiNii Research

Language：Japanese   Publisher：The Japanese Society of Toxicology  

<p>Diabetes is a chronic metabolic disorder that affects nearly 10% of adult people worldwide. It is characterized by high levels of blood glucose, which can lead to a range of complications, such as cardiovascular disease, neuropathy, and retinopathy. Recently, mitochondrial quality control has been highlighted as a potential therapeutic target for treating diabetes and its complications. We previously reported that mitochondrial hyperfission by forming a protein complex between dynamin-related protein (Drp) 1 and filamin A (FLNa), mediates chronic heart failure and cilnidipine, developed as an L/N-type Ca²⁺ channel blocker, improves heart failure by inhibiting Drp1-FLNa protein complex. Therefore, we investigated whether cilnidipine improves hyperglycemia of various diabetic model mice.</p><p>Cilnidipine treatment improved systemic hyperglycemia and mitochondrial morphological abnormalities in STZ-exposed mice, without lowering blood pressure. In contrast, cilnidipine failed to improve hyperglycemia of <i> ob/ob</i> mice, by suppressing insulin secretion. Therefore, we have identified a Ca²⁺channel-insensitive cilnidipine derivative (1,4-DHP) that does not inhibit insulin release. 1,4-DHP improved hyperglycemia and mitochondria morphology abnormality in <i> ob/ob</i> mice fed high-fat diet. These results suggested that maintaining mitochondrial quality by inhibition of Drp1-FLNa becomes a new strategy for diabetes treatment to treat diabetes and diabetic complications.</p>

DOI： 10.14869/toxpt.51.1.0_s8-4

CiNii Research

Language：Japanese   Publisher：The Japanese Society of Toxicology  

<p>The number of cancer patients worldwide is increasing every year. On the other hand, there are still many unknowns regarding the development of cardiovascular disease in cancer patients. Osimertinib is used for treatment of epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer and significantly improves the prognosis. However, heart failure is observed in 1-5% of patients during treatment and QT prolongation in 10%, with a lethal course in some cases, but the mechanism of cardiotoxicity caused by osimertinib has not been elucidated.</p><p>In this study, we focused on the mitochondria of human iPS-derived cardiomyocytes (hiPSC-CMs) to analyze the cardiotoxicity mechanism of osimertinib. Exposure of hiPSC-CMs to anticancer drugs (osimertinib, doxorubicin, and trastuzumab) induced mitochondrial hyperfission and suppressed respiratory capacity. Our laboratory has previously found that sulfur metabolism plays an important role in maintaining mitochondrial quality in cardiomyocytes. When sulfur molecular donors (Na₂S, Na₂S₂, and Na₂S₃) were added, Na₂S most strongly inhibited osimertinib-induced mitochondrial dysfunction. Intracellular imaging using a sulfur molecular detection probe showed that osimertinib reduced intracellular H₂S concentrations, which were restored by Na₂S exposure.</p><p>These results indicate that osimertinib reduces intracellular H₂S levels concurrently with mitochondrial dysfunction in myocardium. Our results also indicate that maintenance of intracellular H₂S levels may contribute to the mitigation of osimertinib cardiotoxicity.</p>

DOI： 10.14869/toxpt.51.1.0_p-139

CiNii Research

Language：Japanese   Publisher：The Japanese Society of Toxicology  

<p>A growing body of evidence suggests that transient receptor potential canonical (TRPC) 3 and 6 channels are involved in developing pathological remodeling of the heart. However, we found that activation of TRPC6 channel enhances β adrenoceptor (βAR)-stimulated myocardial positive inotropy and prevents chronic heart failure in mice by enhancing Zn²⁺ dynamics. This study aims to investigate whether TRPC6-mediated Zn²⁺ influx suppresses sympathetic overactivity-induced chronic heart failure in mice. </p><p>Chronic stimulation of βAR with isoproterenol (ISO; 30 mg/kg/day) for 4 weeks caused myocardial dysfunction in WT mice and Zn²⁺ permeation-dead (PD) TRPC6 mutant-expressing mice. Treatment with 2-[4-(2,3-dimethylphenyl)-piperazin-1-yl]-N- (2-ethoxyphenyl) acetamide (PPZ2), a TRPC3/6/7 channel activator, improved ISO-induced heart failure in WT mice but failed in TRPC6 (PD) mice. Zinpyr-1 imaging revealed that PPZ2 increased the intracellular Zn²⁺ pool in ISO-treated WT hearts, while this increase was not observed in ISO-treated TRPC6 (PD) hearts. In addition, the electrophysiological study demonstrated that TRPC6 (PD) mutant could permeate Na⁺, Ca²⁺ and K⁺ as much as WT, but failed to permeate Zn²⁺ after PPZ2 stimulation. PPZ2 improved ISO-induced impairment of L-type Ca²⁺ channel current. Furthermore, PPZ2 attenuated ISO-induced oxidative stress and supersulfide catabolism. In conclusion, these results suggest that activating TRPC6-mediated Zn²⁺ influx improves chronic heart failure by maintaining redox homeostasis.</p>

DOI： 10.14869/toxpt.51.1.0_p-4s

CiNii Research

Language：Japanese   Publisher：日本心脈管作動物質学会  

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