Progressive atrioventricular conduction defects and heart failure in mice expressing a mutant Csx/Nkx2.5 homeoprotein

Kasahara, Hideko; Wakimoto, Hiroko; Liu, Margaret; Maguire, Colin T.; Converso, Kimber; Shioi, Tetsuo; Huang, Weei‐Yuarn; Manning, Warren J.; Planchard, David; Lawitts, Joel; Berul, Charles I.; Izumo, Seigo

doi:10.1172/jci200112694

Cited by 37 publications

(47 citation statements)

References 38 publications

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“…Post-natal down-regulation of Cx40 was also observed in transgenic mice expressing a mutant of Nkx2.5 homeoprotein. In contrast to Rho GDIα transgenic mice, Cx43 expression was down-regulated in Nkx2.5 mutant mice (40). As Cx43 expression was not altered in Rho GDIα transgenic hearts, these mice represent an interesting model to investigate the mechanisms specifically involved in regulation of Cx40 expression.…”

Section: Discussionmentioning

confidence: 96%

Disruption of Rho signaling results in progressive atrioventricular conduction defects while ventricular function remains preserved

et al. 2004

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Recent studies suggest that RhoA and Rac1 mediate hypertrophic signals in cardiac myocyte hypertrophy. However, effects on cardiac function caused by inhibition of their activity in the heart have yet to be evaluated. Cardiac-specific inhibition of Rho family protein activities was achieved by expressing Rho GDIalpha, an endogenous specific GDP dissociation inhibitor for Rho family proteins, using the alpha-myosin heavy-chain promoter. Increased expression of Rho GDIalpha led to atrial arrhythmias and mild ventricular hypertrophy in adult mice (4-7 months). However, left ventricular systolic and diastolic function was largely preserved before and after the development of cardiac hypertrophy, indicating that Rho GTPases are not required to maintain ventricular contractile function under basal physiological condition. Electrocardiography and intracardiac electrophysiological studies revealed first-degree atrioventricular (AV) block in the transgenic heart at 1 week of age, which further progressed into second-degree AV block at 4 weeks of age before the development of cardiac hypertrophy. Expression of connexin 40 dramatically decreased from 1 week to 4 weeks of age in the transgenic heart, which may contribute in part to the conduction defects in the transgenic mice. This study provides novel evidence for an important role of Rho GTPases in regulating AV conduction.

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Section: Discussionmentioning

confidence: 96%

Disruption of Rho signaling results in progressive atrioventricular conduction defects while ventricular function remains preserved

et al. 2004

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“…Detail procedures for ECG acquisition have been described previously (Gehrmann & Berul, 2000;Kasahara et al, 2001). Briefly, mice were anesthetized with 1.5% isoflurane and the ECG was recorded using six surface leads.…”

Section: Ecg and Mri Heart Analysismentioning

confidence: 99%

Compound loss of muscleblind‐like function in myotonic dystrophy

Lee¹,

Li²,

Manchanda³

et al. 2013

EMBO Mol Med

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Myotonic dystrophy (DM) is a multi-systemic disease that impacts cardiac and skeletal muscle as well as the central nervous system (CNS). DM is unusual because it is an RNA-mediated disorder due to the expression of toxic microsatellite expansion RNAs that alter the activities of RNA processing factors, including the muscleblind-like (MBNL) proteins. While these mutant RNAs inhibit MBNL1 splicing activity in heart and skeletal muscles, Mbnl1 knockout mice fail to recapitulate the full-range of DM symptoms in these tissues. Here, we generate mouse Mbnl compound knockouts to test the hypothesis that Mbnl2 functionally compensates for Mbnl1 loss. Although Mbnl1−/−; Mbnl2−/− double knockouts (DKOs) are embryonic lethal, Mbnl1−/−; Mbnl2+/− mice are viable but develop cardinal features of DM muscle disease including reduced lifespan, heart conduction block, severe myotonia and progressive skeletal muscle weakness. Mbnl2 protein levels are elevated in Mbnl1−/− knockouts where Mbnl2 targets Mbnl1-regulated exons. These findings support the hypothesis that compound loss of MBNL function is a critical event in DM pathogenesis and provide novel mouse models to investigate additional pathways disrupted in this RNA-mediated disease.

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“…The homeodomain-containing transcription factor Csx/NKx2.5 (a member of the NK2-class homeodomain protein and an early cardiogenic marker) is also considered to be involved in the regulation of connexins 40 and 43. Thus, mutation of the Csx/Nkx2.5 (I183P) in mice led to a marked downregulation of both Cx40 and Cx43 (Kasahara et al, 2001). The authors concluded that connexins may be direct or indirect downstream targets of Csx/NKx2.5.…”

Section: General Considerationsmentioning

confidence: 99%

Pharmacological modulation and differential regulation of the cardiac gap junction proteins connexin 43 and connexin 40

Dhein

Polontchouk

Salameh³

et al. 2002

Biology of the Cell

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Gap junction channels provide the basis for the electrical syncytial properties of the heart as a communicating electrical network. Cardiac gap junction channels are predominantly composed of connexin 40 or connexin 43. The conductance of these channels (g(j)) can be regulated pharmacologically: substances which activate protein kinase C, protein kinase A or protein kinase G may alter Cx43 gap junction conductance. However, for PKC, this seems to be subtype specific. Thus, antiarrhythmic peptides can enhance g(j) via activation of PKCepsilon, while FGF-2 reduces g(j) via PKCepsilon. Lipophilic drugs can uncouple the channels. Besides an acute regulation of g(j), the expression of the cardiac connexins can also be regulated. A decrease in Cx43 with a concomitant increase in Cx40 has been found in end-stage failing hearts, while in renovascular hypertension, an increase in Cx43 has been described. Mediators like endothelin-1, angiotensin-II, TGF-beta, VEGF, and cAMP have been shown to increase Cx43. Interestingly, endothelin-1 and angiotensin-II increased Cx43 but did not affect Cx40 expression. In contrast, in humans suffering from atrial fibrillation (AF), the content in Cx40 can be enhanced while Cx43 was unaltered, although in several other studies, other changes of the cardiac connexins were found, which might be related to the type of AF. Regarding the role of calcium, the content in both Cx40 and Cx43 was decreased in cultured neonatal rat cardiomyocytes after 24 h administration of 100 nM verapamil. Thus, gap junctional channels can be affected pharmacologically either acutely by modulating gap junction conductance or chronically by altering gap junction protein expression. Interestingly, it appears that the expression of Cx43 and Cx40 can be differentially regulated.

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Progressive atrioventricular conduction defects and heart failure in mice expressing a mutant Csx/Nkx2.5 homeoprotein

Cited by 37 publications

References 38 publications

Disruption of Rho signaling results in progressive atrioventricular conduction defects while ventricular function remains preserved

Disruption of Rho signaling results in progressive atrioventricular conduction defects while ventricular function remains preserved

Compound loss of muscleblind‐like function in myotonic dystrophy

Pharmacological modulation and differential regulation of the cardiac gap junction proteins connexin 43 and connexin 40

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