Tumor Necrosis Factor-.ALPHA. Downregulates the Voltage Gated Outward K+ Current in Cultured Neonatal Rat Cardiomyocytes  A Possible Cause of Electrical Remodeling in Diseased Hearts

Kawada, Hideaki; Niwano, Shinichi; Niwano, Hiroe; Yumoto, Yoshihiro; Wakisaka, Yoshinari; Yuge, Masaru; Kawahara, Katsumasa; Izumi, Tohru

doi:10.1253/circj.70.605

Cited by 58 publications

(42 citation statements)

References 26 publications

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“…31, 32 We previously reported that TNF-α stimulation downregulates the voltage gated outward K + current in cultured neonatal rat cardiomyosytes, 12 and Higuchi et al reported that NAC inhibited TNF-α-induced cellular hypertrophy and increased protein synthesis. 33 Considering the results of these reports, ROS activation can be considered to play an important role in promoting ventricular remodeling in the inflammatory condition.…”

Section: Role Of Oxidative Stress In Electrical Remodelingmentioning

confidence: 96%

“…10, 11 We have also reported that TNF-α stimulation induces cellular hypertrophy as well as suppression of the Ito current and Kv4.2 expression in cultured neonatal rat myocytes. 12 Because TNF-α is a strong inducer of nitric oxide (NO) or reactive oxygen species (ROS), this inflammatory process may promote cardiac injury and electrical remodeling through a hyper-oxidative condition. Several studies have documented that antioxidant treatment using N-acetylcysteine (NAC), a thiol-containing radical scavenger and glutathione precursor, may attenuate the myocardial damage through in vitro and in vivo models of heart diseases, 13-15 so that the anti-remodeling effect of antioxidant therapy might be expected in myocarditis.…”

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N-Acetylcysteine Suppresses the Progression of Ventricular Remodeling in Acute Myocarditis - Studies in an Experimental Autoimmune Myocarditis (EAM) Model -

Niwano

Sasaki

et al. 2011

Circ J

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Circulation Journal Official Journal of the Japanese Circulation Society http://www. j-circ.or.jp lectrical and structural remodeling of the heart can develop in various pathological conditions, such as myocardial ischemia, 1-3 cardiomyopathy, 4,5 congestive heart failure, 3,6 hypertension 7 as well as myocarditis. 8, 9 In previous reports, we documented ventricular electrical and structural remodeling in an experimental autoimmune myocarditis (EAM) model in rats, 8,9 and it was characterized by prolongation in the effective refractory period (ERP) and monophasic action potential duration (MAPD) and downregulated expressions of the Kv4.2, Kv1.5, potassium channel interacting protein-2 (KChIP2) and sarcoplasmic reticulum Ca 2+ -ATPase 2a (SERCa2a). In this model, the overexpression of inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) or interferon-γ (IFN-γ) induces myocardial damage and possibly causes ventricular remodeling. 10, 11 We have also reported that TNF-α stimulation induces cellular hypertrophy as well as suppression of the Ito current and Kv4.2 expression in cultured neonatal rat myocytes. 12 Because TNF-α is a strong inducer of nitric oxide (NO) or reactive oxygen species (ROS), this inflammatory process may promote cardiac injury and electrical remodeling through a hyper-oxidative condition. Several studies have documented that antioxidant treatment using N-acetylcysteine (NAC), a thiol-containing radical scavenger and glutathione precursor, may attenuate the myocardial damage through in vitro and in vivo models of heart diseases, 13-15 so that the anti-remodeling effect of antioxidant therapy might be expected in myocarditis. In the present study, we evaluated the expression of inflammatory cytokines and ROS generation through the development of cardiac remodeling in an EAM rat model, and also evaluated the effect of NAC as an antioxidative therapy for ventricular electrical and structural remodeling. Background: Electrical and structural remodeling, characterized by prolonged action potential duration (APD), Kv4.2 downregulation and cellular infiltration were studied in rat experimental autoimmune myocarditis (EAM). Because the reactive oxygen species (ROS) has been speculated to play a role in the promotion of such remodeling, the effect of N-acetylcysteine (NAC) on the progression of ventricular remodeling was evaluated.

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Section: Role Of Oxidative Stress In Electrical Remodelingmentioning

confidence: 96%

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N-Acetylcysteine Suppresses the Progression of Ventricular Remodeling in Acute Myocarditis - Studies in an Experimental Autoimmune Myocarditis (EAM) Model -

Niwano

Sasaki

et al. 2011

Circ J

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“…Tissue fibrosis was evaluated by Azan staining, and fibrosis was expressed as the mean -%area on digitized images. 16,17 Quantitative Real-Time Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR)…”

Section: Histologymentioning

confidence: 99%

Inhomogenic Effect of Bepridil on Atrial Electrical Remodeling in a Canine Rapid Atrial Stimulation Model

Fukaya

Niwano

Satoh

et al. 2008

Circ J

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BackgroundThe antiarrhythmic or reverse remodeling effects of bepridil, a multi-ion channel blocker, have been recently reported, but inhomogeneity of the electrical remodeling and effects of bepridil have been observed in previous reports. In this study, the effect of long-term administration of bepridil on atrial electrical remodeling was evaluated in a comparison of the right and left atrium (RA and LA) in a canine rapid atrial stimulation model. Methods and ResultsIn 10 beagle dogs, rapid atrial pacing (400 beats/min) was delivered for 6 weeks and the atrial effective refractory period (AERP), conduction velocity (CV) and inducibility of atrial fibrillation (AF) were evaluated every week. In 5 of the pacing dogs, bepridil (10 mg·kg -1 ·day -1 ) was administered orally, starting 2 weeks after the initiation of the rapid pacing. At the end of the protocol, the hemodynamic parameters and extent of tissue fibrosis were evaluated and the mRNA of SCN5A, Kv4.3, the L-type Ca 2+ channel (LCC) and connexin (Cx) 40, 43, and 45 in both atria were examined by quantitative real-time reverse transcriptase-polymerase chain reaction. In the pacing control group, AERP shortening, decreased CV, increased AF inducibility and downregulation of the expression of SCN5A and LCC were observed. In the bepridil group, the AERP exhibited a relatively quick recovery after bepridil was started in the first week and continued to recover gradually until the end of the protocol, but that recovery was smaller in the LA than in the RA. The CV was not affected by bepridil administration. AF inducibility was well suppressed in the RA in the bepridil group, but the induction of short-duration AF could not be suppressed in the LA. The mRNA downregulation of the LCC and SCN5A was negated by bepridil administration in the RA; but not in the LA; however, the data showed similar tendencies. There were no significant differences in the hemodynamic parameters or tissue fibrosis and the mRNA expression of Kv4.3, Cx40, 43, and 45 between the pacing control and bepridil groups. Conclusion Bepridil exhibited an anti-electrical remodeling effect in this study as previously reported, but the effect was inhomogeneous between the RA and LA, with the LA appearing to be more resistant to the effect of bepridil. (Circ J 2008; 72: 318 -326)

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“…Nonetheless, to date, the effects of these cytokines on ion channels and electrical properties of the heart and how they contribute to rhythm disturbances is a topic that remains incompletely understood. In a few studies examining the role of TNF␣ on K ϩ currents, it was concluded that TNF␣ reduced the current density and expression of the Ca 2ϩ -independent transient outward K ϩ current (I to ), K ϩ channel-interacting protein-2 (KChIP-2), and ultrarapid delayed rectifier K ϩ current (I Kur ) (15)(16)(17). However, most of these studies used a concentration of TNF␣ in the "ng/ml" range, i.e.…”

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Interleukin-1β Reduces L-type Ca2+ Current through Protein Kinase Cϵ Activation in Mouse Heart

Khoury

Mathieu

Fiset

2014

Journal of Biological Chemistry

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Background: Cytokines are important inflammatory mediators that can affect cardiac function. Results: Treatment with IL-1␤ but not TNF␣ reduced the density of L-type Ca 2ϩ current. Conclusion: Mechanisms underlying IL-1␤ effects implicate oxidative stress and PKC⑀ signaling to alter L-type Ca 2ϩ current. Significance: Elucidating the cytokine signaling pathways are important in understanding their role in heart disease.

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Tumor Necrosis Factor-.ALPHA. Downregulates the Voltage Gated Outward K+ Current in Cultured Neonatal Rat Cardiomyocytes A Possible Cause of Electrical Remodeling in Diseased Hearts

Cited by 58 publications

References 26 publications

N-Acetylcysteine Suppresses the Progression of Ventricular Remodeling in Acute Myocarditis - Studies in an Experimental Autoimmune Myocarditis (EAM) Model -

N-Acetylcysteine Suppresses the Progression of Ventricular Remodeling in Acute Myocarditis - Studies in an Experimental Autoimmune Myocarditis (EAM) Model -

Inhomogenic Effect of Bepridil on Atrial Electrical Remodeling in a Canine Rapid Atrial Stimulation Model

Interleukin-1β Reduces L-type Ca2+ Current through Protein Kinase Cϵ Activation in Mouse Heart

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