title: TGF-β1-mediated fibrosis and ion channel remodeling are key mechanisms in producing the sinus node dysfunction associated with SCN5A deficiency and aging.
abstract: BACKGROUND
  Mutations in the cardiac Na(+) channel gene (SCN5A) can adversely affect electric function in the heart, but effects can be age dependent. We explored the interacting effects of Scn5a disruption and aging on the pathogenesis of sinus node dysfunction in a heterozygous Scn5a knockout (Scn5a(+/-)) mouse model.
  
  
  RESULTS
  We compared functional, histological, and molecular features in young (3 to 4 month) and old (1 year) wild type and Scn5a(+/-) mice. Both Scn5a disruption and aging were associated with decreased heart rate variability, reduced sinoatrial node automaticity, and slowed sinoatrial conduction. They also led to increased collagen and fibroblast levels and upregulated transforming growth factor-β(1) (TGF-β(1)) and vimentin transcripts, providing measures of fibrosis and reduced Nav1.5 expression. All these effects were most noticeable in old Scn5a(+/-) mice. Na(+) channel inhibition by Nav1.5-E3 antibody directly increased TGF-β(1) production in both cultured human cardiac myocytes and fibroblasts. Finally, aging was associated with downregulation of a wide range of ion channel and related transcripts and, again, was greatest in old Scn5a(+/-) mice. The quantitative results from these studies permitted computer simulations that successfully replicated the observed sinoatrial node phenotypes shown by the different experimental groups.
  
  
  CONCLUSIONS
  These results implicate a tissue degeneration triggered by Nav1.5 deficiency manifesting as a TGF-β(1)-mediated fibrosis accompanied by electric remodeling in the sinus node dysfunction associated with Scn5a disruption or aging. The latter effects interact to produce the most severe phenotype in old Scn5a(+/-) mice. In demonstrating this, our findings suggest a novel regulatory role for Nav1.5 in cellular biological processes in addition to its electrophysiologic function.
authors.affiliation: School of Biomedicine, University of Manchester, UK.
authors.forename: Xiaojin
authors.initials: X
authors.lastname: Hao
authors.forename: Yanmin
authors.initials: Y
authors.lastname: Zhang
authors.forename: Xinzhao
authors.initials: X
authors.lastname: Zhang
authors.forename: Mahesh
authors.initials: M
authors.lastname: Nirmalan
authors.forename: Laura
authors.initials: L
authors.lastname: Davies
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Konstantinou
authors.forename: Fei
authors.initials: F
authors.lastname: Yin
authors.forename: Halina
authors.initials: H
authors.lastname: Dobrzynski
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Andrew
authors.initials: A
authors.lastname: Grace
authors.forename: Henggui
authors.initials: H
authors.lastname: Zhang
authors.forename: Mark
authors.initials: M
authors.lastname: Boyett
authors.forename: Christopher L-H
authors.initials: CL
authors.lastname: Huang
authors.forename: Ming
authors.initials: M
authors.lastname: Lei
mesh_terms: D000375:Aging / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D003198:Computer Simulation; D004195:Disease Models, Animal; D006321:Heart / Q000196:embryology; D006329:Heart Conduction System / Q000378:metabolism / Q000503:physiopathology*; D006801:Humans; D007150:Immunohistochemistry; D015640:Ion Channel Gating; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism*; D062554:NAV1.5 Voltage-Gated Sodium Channel; D016133:Polymerase Chain Reaction; D012313:RNA / Q000235:genetics*; D012804:Sick Sinus Syndrome / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D012849:Sinoatrial Node / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D015222:Sodium Channels / Q000172:deficiency / Q000235:genetics*
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; C568321:Scn5a protein, mouse; D015222:Sodium Channels; D012313:RNA