Mouse model of SCN5A-linked hereditary Lenègre's disease: age-related conduction slowing and myocardial fibrosis.
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.


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 beta-MHC and skeletal alpha-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.
Royer
Anne
A
INSERM U533, Institut du Thorax, Faculté de Médecine, Nantes, France.
van Veen
Toon A B
TA
Le Bouter
Sabrina
S
Marionneau
Céline
C
Griol-Charhbili
Violaine
V
Léoni
Anne-Laure
AL
Steenman
Marja
M
van Rijen
Harold V M
HV
Demolombe
Sophie
S
Goddard
Catharine A
CA
Richer
Christine
C
Escoubet
Brigitte
B
Jarry-Guichard
Thérèse
T
Colledge
William H
WH
Gros
Daniel
D
de Bakker
Jacques M T
JM
Grace
Andrew A
AA
Escande
Denis
D
Charpentier
Flavien
F
D000367:Age Factors; D000818:Animals; D006332:Cardiomegaly; D017630:Connexins / Q000032:analysis; D004195:Disease Models, Animal; D004562:Electrocardiography; D005355:Fibrosis / Q000235:genetics; D005786:Gene Expression Regulation; D030342:Genetic Diseases, Inborn; D006327:Heart Block / Q000209:etiology / Q000235:genetics*; D006329:Heart Conduction System / Q000503:physiopathology*; D006352:Heart Ventricles / Q000473:pathology; D006579:Heterozygote; D051379:Mice; D018345:Mice, Knockout; D062554:NAV1.5 Voltage-Gated Sodium Channel; D015222:Sodium Channels / Q000235:genetics*; D014157:Transcription Factors / Q000032:analysis
D017630:Connexins; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568321:Scn5a protein, mouse; D015222:Sodium Channels; D014157:Transcription Factors