ETV1 activates a rapid conduction transcriptional program in rodent and human cardiomyocytes

Abstract

Rapid impulse propagation is a defining attribute of the pectinated atrial myocardium and His-Purkinje system (HPS) that safeguards against atrial and ventricular arrhythmias, conduction block, and myocardial dyssynchrony. The complex transcriptional circuitry that dictates rapid conduction remains incompletely understood. Here, we demonstrate that ETV1 (ER81)-dependent gene networks dictate the unique electrophysiological characteristics of atrial and His-Purkinje myocytes. Cardiomyocyte-specific deletion of ETV1 results in cardiac conduction abnormalities, decreased expression of rapid conduction genes (Nkx2–5, Gja5, and Scn5a), HPS hypoplasia, and ventricularization of the unique sodium channel properties that define Purkinje and atrial myocytes in the adult heart. Forced expression of ETV1 in postnatal ventricular myocytes (VMs) reveals that ETV1 promotes a HPS gene signature while diminishing ventricular and nodal gene networks. Remarkably, ETV1 induction in human induced pluripotent stem cell-derived cardiomyocytes increases rapid conduction gene expression and inward sodium currents, converting them towards a HPS phenotype. Our data identify a cardiomyocyte-autonomous, ETV1-dependent pathway that is responsible for specification of rapid conduction zones in the heart and demonstrate that ETV1 is sufficient to promote a HPS transcriptional and functional program upon VMs.

The Nucleocapsid Protein of SARS-CoV-2 Abolished Pluripotency in Human Induced Pluripotent Stem Cells

“…The split ratio was 1:3-1:6. The detailed differentiation protocol was described in the previous published reports [31,32]. Briefly, iPSC were…”

New Mathematical Models for the Mouse Atrial Fast Sodium Channel

“…Because of different experiment conditions, data points need to be adjusted for two reasons before usage: temperature adjustment from room temperature to body temperature, and time adjustment for the shifted activation and inactivation curve along with time after the patch rupture. Therefore, the experiment data from Shekhar et al and Cerrone et al [9], [10] were first adjust with +12 mV from room temperature to body temperature (the V1/2 of the activation gate was moved from -57 mV at 16 ℃ to -49 mV at 26 ℃ reported by Murray et al [11], and linearity of the change was assumed). Then the data from Shekhar et al was further moved by +1.6 mV since the average patch life in their experiments was 15 min and it was reported that in guinea pig atria the activation curve of FSC move about +3.2 mV per 1/2 hour [12].…”

“…It has been found in experiments that the conductance of FSC in atria is bigger than that in ventricles. The maximum conductance was 1.14 ± 0.07 nS/pF in right atria and 0.92 ± 0.04 nS/pF in ventricles [9]. Also considering the maximum upstroke velocity should be around 200 V/s and the overshoot about +20 mV, we set the conductance of the FSC to 1.2 nS/pF at room temperature.…”

“…On the other hand, recent experiments have shown that there are obvious discrepancies in FSC kinetics between ventricles and atria. Shekhar et al [8], [9] found that the sodium current in mouse right atria shows a larger whole cell current, and the activation and inactivation curve are all shifted to lower membrane potentials then that in mouse ventricles.…”

Angiotensin II induces apoptosis in human induced pluripotent stem cell-derived cardiomyocytes

“…Heart failure (HF) is the most popular chronic disease among the elderly 79 in developed countries (1), and its prevalence and incidence is increasing 80 in the resent years (2-4). Approximately 26 million individuals are 81 suffering HF worldwide (5), in which the survival rate within 5 years of 82 admission was less than 53% (6-8). The chronic heart failure causes a 83 tremendous economic burden with an estimation of $108 billion per year 84 globally (9).…”