The Timing of Myocardial Trpm7 Deletion during Cardiogenesis Variably Disrupts Adult Ventricular Function, Conduction and Repolarization
Background—Transient Receptor Potential (TRP) channels are a superfamily of broadly expressed ion channels with diverse physiological roles. TRPC1, 3 and 6 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.
Methods and Results—We generated multiple cardiac-targeted knock-out mice to test the hypothesis that TRPM7 is required for normal ventricular function. Early cardiac Trpm7-deletion (<E9, TnT/Isl1-Cre) results in congestive heart failure and death by E11.5 due to hypo-proliferation of the compact myocardium. Remarkably, Trpm7-deletion late in cardiogenesis (~E13, 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.
- Received December 20, 2012.
- Revision received April 19, 2013.
- Accepted May 29, 2013.