Heterogeneous Loss of Connexin43 Protein in Nonischemic Dilated Cardiomyopathy with Ventricular Tachycardia

Kitamura, Hidetsuna; Ohnishi, Yozo; Yoshida, Akihiro; Okajima, Katsunori; Azumi, Hiroshi; Ishida, Akihiko; Galeano, Erdulfo J.; Kubo, Shinya; Hayashi, Yoshitake; Itoh, Hiroshi; Yokoyama, Mitsuhiro

doi:10.1046/j.1540-8167.2002.00865.x

Cited by 96 publications

(63 citation statements)

References 7 publications

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“…facilitated reentry. 16,17 Furthermore, MAPK activation and Cx43 downregulation may be connected, as constitutively activated p-jnk potently reduces Cx43 levels in mouse myocardium, and p-erk has been implicated in Cx43 downregulation in liver epithelial cells. 18,19 Ongoing studies are addressing the physiological importance of the expression changes revealed in the present study, as well as expanding the analysis by means of subproteomic and transcriptome analysis.…”

Section: Discussionmentioning

confidence: 99%

Regional Alterations in Protein Expression in the Dyssynchronous Failing Heart

et al. 2003

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Background-Left ventricular (LV) mechanical dyssynchrony induces regional heterogeneity of mechanical load and is an independent predictor of mortality and sudden death in heart failure (HF) patients. We tested whether dyssynchrony also induces localized disparities in the expression of proteins involved with mechanical stress, function, and arrhythmia susceptibility. Methods and Results-Eleven dogs underwent tachycardia-induced HF pacing, either from the right atrium or high right ventricular free wall. Whereas global LV dysfunction was similar between groups, LV contractile coordination assessed by tagged MRI was markedly dyssynchronous with right ventricular pacing but synchronous with right atrial pacing. In dyssynchronous failing hearts, the lateral LV endocardium displayed a 2-fold increase in phosphorylated erk mitogen-activated protein kinase expression (with no change in phospho-p38 or phospho-jnk), a 30% decline in sarcoplasmic reticulum Ca 2ϩ -ATPase, an 80% reduction in phospholamban, and a 60% reduction in the gap junction protein connexin43, relative to neighboring myocardial segments. In contrast, hearts from both right atrial-paced HF dogs and an additional 4 noninstrumented control animals showed minimal regional variability in protein expression. Conclusions-LV dyssynchrony in failing hearts generates myocardial protein dysregulation concentrated in the late-activated, high-stress lateral endocardium. Such molecular polarization within the LV creates transmural and transchamber expression gradients of calcium handling and gap junction proteins that may worsen chamber function and arrhythmia susceptibility. Key Words: heart failure Ⅲ pacing Ⅲ molecular biology Ⅲ sarcoplasmic reticulum T he pathophysiology of heart failure (HF) involves abnormalities of stress response kinase signaling, neurohumoral stimulation, excitation-contraction coupling, gap junction and ion channel function, and chamber remodeling. 1,2 In addition, recent studies have shown that left ventricular (LV) mechanical coordination is frequently disturbed in HF, particularly in the setting of interventricular conduction delay. HF patients with interventricular conduction delay and concomitant ventricular dyssynchrony have mortality and sudden cardiac death rates above those predicted from the apparent severity of systolic dysfunction, HF etiology, functional class, or concurrent medical therapy. 3,4 Acute mechanical discoordination induced by single-site right ventricular (RV) or LV pacing depresses systolic function, worsens myocardial efficiency, and leads to marked increases in wall stress heterogeneity. 5,6 Stress is highest in late-activated myocardial regions because of both exaggerated stretch in early systole (secondary to septal contraction) and late systolic contraction against increased afterload. Chronic discoordination leads to chamber remodeling of both early-and late-activated segments. 7 However, its effect on myocardial protein expression remains unknown. In the present study, we tested the hypothesis that stress...

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Section: Discussionmentioning

confidence: 99%

Regional Alterations in Protein Expression in the Dyssynchronous Failing Heart

et al. 2003

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“…Heterogeneous expression of Cx43, however, has been shown to be associated with enhanced susceptibility to arrhythmias in patients, 13 dogs 14,15 and mice. 16 Spatial heterogeneity in Cx43 expression in our study was quantified (as described before) 17 and showed a significantly higher heterogeneous Cx43 expression in TAC operated compared with sham-operated mice.…”

Section: N T E R U N I V E R S I T Y C a R D I O L O G Y I N S T I mentioning

confidence: 99%

Longitudinal arrhythmogenic remodelling in a mouse model of longstanding pressure overload

Boulaksil¹,

Noorman²,

Engelen³

et al. 2010

NHJL

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“…The gap junction channel proteins connexin43, connexin45 and connexin40 are important for cell-to-cell propagation of excitations. Downregulation of connexin43 expression is associated with an increased likelihood of ventricular tachyarrhythmias in heart failure (Kitamura et al, 2002). Other connexins, including connexin45 (Yamada et al, 2003) and connexin40 (Dupont et al, 2001), are upregulated in failing hearts, possibly as a compensation for connexin43 downregulation.…”

Section: Application Of Our Bioinformatics Analysis To Heart Failurementioning

confidence: 99%

MicroRNA Targeting in Heart: A Theoretical Analysis

Wang¹

2011

Bioinformatics - Trends and Methodologies

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Heterogeneous Loss of Connexin43 Protein in Nonischemic Dilated Cardiomyopathy with Ventricular Tachycardia

Abstract: Heterogeneous reduction of Cx43 protein may result in development of malignant ventricular arrhythmia in DCM.

Cited by 96 publications

References 7 publications

Regional Alterations in Protein Expression in the Dyssynchronous Failing Heart

Regional Alterations in Protein Expression in the Dyssynchronous Failing Heart

Longitudinal arrhythmogenic remodelling in a mouse model of longstanding pressure overload

MicroRNA Targeting in Heart: A Theoretical Analysis

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