title: Timing of myocardial trpm7 deletion during cardiogenesis variably disrupts adult ventricular function, conduction, and repolarization.
abstract: BACKGROUND
  Transient receptor potential (TRP) channels are a superfamily of broadly expressed ion channels with diverse physiological roles. TRPC1, TRPC3, and TRPC6 are believed to contribute to cardiac hypertrophy in mouse models. Human mutations in TRPM4 have been linked to progressive familial heart block. TRPM7 is a divalent-permeant channel and kinase of unknown function, recently implicated in the pathogenesis of atrial fibrillation; however, its function in ventricular myocardium remains unexplored.
  
  
  RESULTS
  We generated multiple cardiac-targeted knockout mice to test the hypothesis that TRPM7 is required for normal ventricular function. Early cardiac Trpm7 deletion (before embryonic day 9; TnT/Isl1-Cre) results in congestive heart failure and death by embryonic day 11.5 as a result of hypoproliferation of the compact myocardium. Remarkably, Trpm7 deletion late in cardiogenesis (about embryonic day 13; αMHC-Cre) produces viable mice with normal adult ventricular size, function, and myocardial transcriptional profile. Trpm7 deletion at an intermediate time point results in 50% of mice developing cardiomyopathy associated with heart block, impaired repolarization, and ventricular arrhythmias. Microarray analysis reveals elevations in transcripts of hypertrophy/remodeling genes and reductions in genes important for suppressing hypertrophy (Hdac9) and for ventricular repolarization (Kcnd2) and conduction (Hcn4). These transcriptional changes are accompanied by action potential prolongation and reductions in transient outward current (Ito; Kcnd2). Similarly, the pacemaker current (If; Hcn4) is suppressed in atrioventricular nodal cells, accounting for the observed heart block.
  
  
  CONCLUSIONS
  Trpm7 is dispensable in adult ventricular myocardium under basal conditions but is critical for myocardial proliferation during early cardiogenesis. Loss of Trpm7 at an intermediate developmental time point alters the myocardial transcriptional profile in adulthood, impairing ventricular function, conduction, and repolarization.
authors.affiliation: Howard Hughes Medical Institute, Department of Cardiology, Manton Center for Orphan Disease, Children's Hospital Boston, 320 Longwood Ave, Enders 1309, Boston, MA 02115, USA.
authors.forename: Rajan
authors.initials: R
authors.lastname: Sah
authors.forename: Pietro
authors.initials: P
authors.lastname: Mesirca
authors.forename: Xenos
authors.initials: X
authors.lastname: Mason
authors.forename: William
authors.initials: W
authors.lastname: Gibson
authors.forename: Christopher
authors.initials: C
authors.lastname: Bates-Withers
authors.forename: Marjolein
authors.initials: M
authors.lastname: Van den Boogert
authors.forename: Dipayan
authors.initials: D
authors.lastname: Chaudhuri
authors.forename: William T
authors.initials: WT
authors.lastname: Pu
authors.forename: Matteo E
authors.initials: ME
authors.lastname: Mangoni
authors.forename: David E
authors.initials: DE
authors.lastname: Clapham
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000367:Age Factors; D000818:Animals; D017353:Gene Deletion; D006329:Heart Conduction System / Q000502:physiology*; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D009206:Myocardium / Q000166:cytology*; D032383:Myocytes, Cardiac / Q000502:physiology*; D050053:TRPM Cation Channels / Q000172:deficiency* / Q000235:genetics; D013997:Time Factors; D016276:Ventricular Function / Q000502:physiology*
chemical_list: D050053:TRPM Cation Channels; C421903:Trpm7 protein, mouse
keywords: electrophysiology; heart block; hypertrophy; ion channels; myocytes, cardiac; potassium channels