Timing of myocardial trpm7 deletion during cardiogenesis variably disrupts adult ventricular function, conduction, and repolarization.
Timing of myocardial trpm7 deletion during cardiogenesis variably disrupts adult ventricular function, conduction, and repolarization.
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DOI：
10.1161/circulationaha.112.000768
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发表时间：
2013-07-09
期刊：
影响因子：
37.8
通讯作者：
Clapham DE
中科院分区：
文献类型：
--
作者：
Sah R;Mesirca P;Mason X;Gibson W;Bates-Withers C;Van den Boogert M;Chaudhuri D;Pu WT;Mangoni ME;Clapham DE
瞬时受体电位（TRP）通道是一个广泛表达的离子通道超家族，具有多种生理功能。TRPC 1、3和6被认为有助于小鼠模型中的心脏肥大。TRPM 4的人类突变与进行性家族性心脏传导阻滞有关。TRPM 7是一种功能未知的二价通透通道和激酶，最近被认为与心房颤动的发病机制有关，但其在心室肌中的功能尚未被研究。我们产生了多个心脏靶向基因敲除小鼠，以测试TRPM 7是正常心室功能所需的假设。早期心脏Trpm 7-缺失（<E9，TnT/Isl 1-Cre）导致充血性心力衰竭，并且由于致密心肌的低增殖导致E11.5时死亡。值得注意的是，在心脏发生晚期（~E13，αMHC-Cre）的Trpm 7缺失产生了具有正常成年心室大小、功能和心肌转录谱的存活小鼠。在中间时间点的TRPM 7缺失导致50%的小鼠发生与心脏传导阻滞、复极受损和室性心律失常相关的心肌病。微阵列分析揭示了肥大/重塑基因转录物的升高和抑制肥大（Hdac 9）和心室复极化（Kcnd 2）和传导（Hcn 4）的重要基因的减少。这些转录变化伴随着动作电位延长和瞬时外向电流（Ito; Kcnd 2）的减少。类似地，起搏器电流（If; Hcn 4）在房室结细胞中被抑制，解释了所观察到的心脏传导阻滞。TRPM 7在基础条件下在成人心室肌中是不稳定的，但在早期心脏发生期间对心肌增殖至关重要。TRPM 7在中间发育时间点的缺失改变了成年期的心肌转录谱，损害心室功能、传导和复极。
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. 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. 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.