Remodeling of Gap Junctions in Mouse Hearts Hypertrophied by Forced Retinoic Acid Signaling

Veen, Toon A.B. van; Rijen, Harold V.M. van; Wiegerinck, Rob F.; Opthof, Tobias; Colbert, Melissa C.; Clément, Sophie; Bakker, Jacques M.T. de; Jongsma, Habo J.

doi:10.1006/jmcc.2002.2102

Cited by 45 publications

(43 citation statements)

References 33 publications

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“…Expression of Cx43 was not globally modified but rather locally altered in the regions with marked fibrosis, a phenomenon that may decrease conduction velocity locally and increase the heterogeneity of propagation. 10 In the mouse model, myocardial rearrangements occurred concomitantly with overexpression of Atf3, a member of the CREB/ATF family of transcription factor genes. Atf3 is normally expressed at very low levels in the heart but is activated by stressors, such as ischemia-reperfusion.…”

Section: Discussionmentioning

confidence: 99%

“…Sections taken from different levels were incubated with antibodies as reported previously. 10 After immunolabeling, sections were mounted in Vectashield (Vector Laboratories) and examined by use of a classic light microscope with epifluorescence equipment (Nikon Optiphot-2). To evaluate the presence of fibrosis, sections were fixed with 4% paraformaldehyde (in PBS, 30 minutes at room temperature) and stained with picrosirius red.…”

Section: Immunohistochemistry and Histologymentioning

confidence: 99%

“…10,12 For the experiments comparing young (14 to 16 weeks old) and old (50 to 73 weeks old) mice, total cellular protein was isolated from 5 hearts (total ventricular section) in each group (young versus old and WT versus Scn5a ϩ/Ϫ ) as described previously. 10 Protein content of the supernatant was assessed according to Lowry's method. Equal amounts (30 g/lane) of each sample were separated on 10% SDS-polyacrylamide gels and transferred by electrophoresis to nitrocellulose membrane (Biorad).…”

Section: Protein Isolation Sds-page and Western Blottingmentioning

confidence: 99%

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Mouse Model of SCN5A -Linked Hereditary Lenègre’s Disease

et al. 2005

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Background— We have previously linked hereditary progressive cardiac conduction defect (hereditary Lenègre’s disease) to a loss-of-function mutation in the gene encoding the main cardiac Na + channel, SCN5A . In the present study, we investigated heterozygous Scn5a -knockout mice ( Scn5a +/− mice) as a model for hereditary Lenègre’s disease. Methods and Results— In Scn5a +/− mice, surface ECG recordings showed age-related lengthening of the P-wave and PR- and QRS-interval duration, coinciding with previous observations in patients with Lenègre’s disease. Old but not young Scn5a +/− mice showed extensive fibrosis of their ventricular myocardium, a feature not seen in wild-type animals. In old Scn5a +/− mice, fibrosis was accompanied by heterogeneous expression of connexin 43 and upregulation of hypertrophic markers, including β-MHC and skeletal α-actin. Global connexin 43 expression as assessed with Western blots was similar to wild-type mice. Decreased connexin 40 expression was seen in the atria. Using pangenomic microarrays and real-time PCR, we identified in Scn5a +/− mice an age-related upregulation of genes encoding Atf3 and Egr1 transcription factors. Echocardiography and hemodynamic investigations demonstrated conserved cardiac function with aging and lack of ventricular hypertrophy. Conclusions— We conclude that Scn5a +/− mice convincingly recapitulate the Lenègre’s disease phenotype, including progressive impairment with aging of atrial and ventricular conduction associated with myocardial rearrangements and fibrosis. Our work provides the first demonstration that a monogenic ion channel defect can progressively lead to myocardial structural anomalies.

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Section: Discussionmentioning

confidence: 99%

Section: Immunohistochemistry and Histologymentioning

confidence: 99%

Section: Protein Isolation Sds-page and Western Blottingmentioning

confidence: 99%

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Mouse Model of SCN5A -Linked Hereditary Lenègre’s Disease

et al. 2005

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“…Sections taken from different levels were incubated with antibodies as reported previously. 9 After immunolabeling, sections were mounted in Vectashield (Vector Laboratories) and examined with a classic light microscope with epifluorescence equipment (Nikon Optiphot-2). To evaluate the presence of fibrosis, sections serial to the ones used for antibody labeling were fixed with 4% paraformaldehyde (in PBS, 30 minutes at room temperature) and stained with Pico Sirius red.…”

Section: Immunohistochemistry and Histologymentioning

confidence: 99%

Impaired Impulse Propagation in Scn5a -Knockout Mice

Veen

Stein²,

Royer³

et al. 2005

Circulation

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Background-The SCN5A sodium channel is a major determinant for cardiac impulse propagation. We used epicardial mapping of the atria, ventricles, and septae to investigate conduction velocity (CV) in Scn5a heterozygous young and old mice. Methods and Results-Mice were divided into 4 groups: (1) young (3 to 4 months) wild-type littermates (WT); (2) young heterozygous Scn5a-knockout mice (HZ); (3) old (12 to 17 months) WT; and (4) old HZ. In young HZ hearts, CV in the right but not the left ventricle was reduced in agreement with a rightward rotation in the QRS axes; fibrosis was virtually absent in both ventricles, and the pattern of connexin43 (Cx43) expression was similar to that of WT mice. In old WT animals, the right ventricle transversal CV was slightly reduced and was associated with interstitial fibrosis. In old HZ hearts, right and left ventricle CVs were severely reduced both in the transversal and longitudinal direction; multiple areas of severe reactive fibrosis invaded the myocardium, accompanied by markedly altered Cx43 expression. The right and left bundle-branch CVs were comparable to those of WT animals. The atria showed only mild fibrosis, with heterogeneously disturbed Cx40 and Cx43 expression. Conclusions-A 50% reduction in

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“…Multiple sections taken from different levels (frontal to dorsal) of the IVS were incubated with primary antibodies directed against Cx40, Cx43, Cx45, ␣-actinin, ␤-catenin, desmin, and N-cadherin as reported previously. 17 After immunolabeling, sections were mounted in Vectashield (Vector Laboratories) and examined with a light microscope equipped for epifluorescence (Nikon Optiphot-2) or by confocal laser scanning microscopy (Nikon RCM-8000 Real Time Laser Confocal Microscope). Staining for acetylcholine esterase (AchE) activity was performed on unfixed septa by incubation (37°C, dark) in 0.…”

Section: Immunohistochemistry and Histologymentioning

confidence: 99%

Discontinuous Conduction in Mouse Bundle Branches Is Caused by Bundle-Branch Architecture

et al. 2005

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Background-Recordings of the electrical activity of mouse bundle branches (BBs) suggest reduced conduction velocity (CV) in the midseptal compared with the proximal part of the BB. The present study was performed to elucidate the mechanism responsible for this slowing of conduction. Methods and Results-Hearts of 16 mice were isolated and Langendorff perfused. After the right and left ventricular free walls were removed, the extracellular activity of the BB was mapped with a 247-point electrode. Premature stimulation was used to estimate CV restitution in the BBs. Expression/distribution of connexin40 (Cx40), Cx43, and Cx45 was determined. Morphology of the conduction system was assessed by whole-mount acetylcholine esterase staining and in Cx40 ϩ/KI-GFP hearts. Effective CV in the midseptal part of the left and right BBs was reduced by 50% compared with the proximal BB. CV restitution in the proximal and midseptal parts of the BBs was similar. Myocytes labeled positive for Cx40 and Cx45 in the entire BB. Cx43 colocalized with Cx40 and Cx45 only in the very distal BB. Subcellular distribution of gap junctions differed between proximal and distal BBs. Geometry of the midseptal and distal BBs revealed on both sides a profuse network of interlacing fibers, whereas the proximal BB consisted of a single (right BB) or multiple (left BB) parallel fibers. Conclusions-Comparison of connexin expression/distribution, geometry of the BBs, and CV characteristics suggests that increased path length for activation resulting from BB geometry is responsible for the apparently reduced CV in the midseptal BB of the mouse heart. (Circulation. 2005;112:2235-2244.)

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Remodeling of Gap Junctions in Mouse Hearts Hypertrophied by Forced Retinoic Acid Signaling

Cited by 45 publications

References 33 publications

Mouse Model of SCN5A -Linked Hereditary Lenègre’s Disease

Mouse Model of SCN5A -Linked Hereditary Lenègre’s Disease

Impaired Impulse Propagation in Scn5a -Knockout Mice

Discontinuous Conduction in Mouse Bundle Branches Is Caused by Bundle-Branch Architecture

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