Transforming growth factor β receptor inhibition prevents ventricular fibrosis in a mouse model of progressive cardiac conduction disease.
OBJECTIVE
Loss-of-function mutations in SCN5A, the gene encoding NaV1.5 channel, have been associated with inherited progressive cardiac conduction disease (PCCD). We have proposed that Scn5a heterozygous knock-out (Scn5a+/-) mice, which are characterized by ventricular fibrotic remodelling with ageing, represent a model for PCCD. Our objectives were to identify the molecular pathway involved in fibrosis development and prevent its activation.


RESULTS
Our study shows that myocardial interstitial fibrosis occurred in Scn5a+/- mice only after 45 weeks of age. Fibrosis was triggered by transforming growth factor β (TGF-β) pathway activation. Younger Scn5a+/- mice were characterized by a higher connexin 43 expression than wild-type (WT) mice. After the age of 45 weeks, connexin 43 expression decreased in both WT and Scn5a+/- mice, although the decrease was larger in Scn5a+/- mice. Chronic inhibition of cardiac sodium current with flecainide (50 mg/kg/day p.o) in WT mice from the age of 6 weeks to the age of 60 weeks did not lead to TGF-β pathway activation and fibrosis. Chronic inhibition of TGF-β receptors with GW788388 (5 mg/kg/day p.o.) in Scn5a+/- mice from the age of 45 weeks to the age of 60 weeks prevented the occurrence of fibrosis. However, current data could not detect reduction in QRS duration with GW788388.


CONCLUSIONS
Myocardial fibrosis secondary to a loss of NaV1.5 is triggered by TGF-β signalling pathway. Those events are more likely secondary to the decreased NaV1.5 sarcolemmal expression rather than the decreased Na+ current per se. TGF-β receptor inhibition prevents age-dependent development of ventricular fibrosis in Scn5a+/- mouse.
INSERM, UMR1087, l'institut du thorax, quai Moncousu, Nantes F-44000, France.|CNRS, UMR6291, quai Moncousu, Nantes F-44000, France.|Université de Nantes, quai Moncousu, Nantes F-44000, France.
Mickael
M
Derangeon
INSERM, UMR1087, l'institut du thorax, quai Moncousu, Nantes F-44000, France.|CNRS, UMR6291, quai Moncousu, Nantes F-44000, France.|Université de Nantes, quai Moncousu, Nantes F-44000, France.
Jérôme
J
Montnach
INSERM, UMR1087, l'institut du thorax, quai Moncousu, Nantes F-44000, France.|CNRS, UMR6291, quai Moncousu, Nantes F-44000, France.|Université de Nantes, quai Moncousu, Nantes F-44000, France.
Cynthia Ore
CO
Cerpa
INSERM, UMR1087, l'institut du thorax, quai Moncousu, Nantes F-44000, France.|CNRS, UMR6291, quai Moncousu, Nantes F-44000, France.|Université de Nantes, quai Moncousu, Nantes F-44000, France.
Benoit
B
Jagu
INSERM, UMR1087, l'institut du thorax, quai Moncousu, Nantes F-44000, France.|CNRS, UMR6291, quai Moncousu, Nantes F-44000, France.|Université de Nantes, quai Moncousu, Nantes F-44000, France.
Justine
J
Patin
INSERM, UMR1087, l'institut du thorax, quai Moncousu, Nantes F-44000, France.|CNRS, UMR6291, quai Moncousu, Nantes F-44000, France.|Université de Nantes, quai Moncousu, Nantes F-44000, France.
Gilles
G
Toumaniantz
INSERM, UMR1087, l'institut du thorax, quai Moncousu, Nantes F-44000, France.|CNRS, UMR6291, quai Moncousu, Nantes F-44000, France.|Université de Nantes, quai Moncousu, Nantes F-44000, France.
Aurore
A
Girardeau
The Section of Cardiovascular Biology, Departments of Biochemistry and Physiology, University of Cambridge, Downing street, Cambridge CB23EG, UK.
Christopher L H
CLH
Huang
The Section of Cardiovascular Biology, Departments of Biochemistry and Physiology, University of Cambridge, Downing street, Cambridge CB23EG, UK.
William H
WH
Colledge
The Section of Cardiovascular Biology, Departments of Biochemistry and Physiology, University of Cambridge, Downing street, Cambridge CB23EG, UK.
Andrew A
AA
Grace
INSERM, UMR1087, l'institut du thorax, quai Moncousu, Nantes F-44000, France.|CNRS, UMR6291, quai Moncousu, Nantes F-44000, France.|Université de Nantes, quai Moncousu, Nantes F-44000, France.
Isabelle
I
Baró
INSERM, UMR1087, l'institut du thorax, quai Moncousu, Nantes F-44000, France.|CNRS, UMR6291, quai Moncousu, Nantes F-44000, France.|Université de Nantes, quai Moncousu, Nantes F-44000, France.|CHU Nantes, Alexis Ricordeau, Nantes F-44000, France.
Flavien
F
Charpentier
D000367:Age Factors; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001145:Arrhythmias, Cardiac / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D001549:Benzamides / Q000494:pharmacology*; D009202:Cardiomyopathies / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D018031:Connexin 43 / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005355:Fibrosis; D005424:Flecainide / Q000494:pharmacology; D020022:Genetic Predisposition to Disease; D006329:Heart Conduction System / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D006339:Heart Rate; D006352:Heart Ventricles / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D006579:Heterozygote; D007700:Kinetics; D008297:Male; D008564:Membrane Potentials; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000172:deficiency / Q000235:genetics; D010641:Phenotype; D011720:Pyrazoles / Q000494:pharmacology*; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000378:metabolism; D020257:Ventricular Remodeling / Q000187:drug effects*; D061567:Voltage-Gated Sodium Channel Blockers / Q000494:pharmacology
C509927:4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)-N-(tetrahydro-2H-pyran-4-yl)benzamide; D000889:Anti-Arrhythmia Agents; D001549:Benzamides; D018031:Connexin 43; C543076:GJA1 protein, mouse; D062554:NAV1.5 Voltage-Gated Sodium Channel; D011720:Pyrazoles; D018125:Receptors, Transforming Growth Factor beta; C568321:Scn5a protein, mouse; D016212:Transforming Growth Factor beta; D061567:Voltage-Gated Sodium Channel Blockers; D005424:Flecainide
CTGF; Connexin 43; GW788388; NaV1.5; Smad2/3