Endothelial deletion of PTBP1 disrupts ventricular chamber development.

The growth and maturation of the ventricular chamber require spatiotemporally precise synergy between diverse cell types. Alternative splicing deeply affects the processes. However, the functional properties of alternative splicing in cardiac development are largely unknown. Our study reveals that an alternative splicing factor polypyrimidine tract-binding protein 1 (PTBP1) plays a key role in ventricular chamber morphogenesis. During heart development, PTBP1 colocalizes with endothelial cells but is almost undetectable in cardiomyocytes. The endothelial-specific knockout of Ptbp1, in either endocardial cells or pan-endothelial cells, leads to a typical phenotype of left ventricular noncompaction (LVNC). Mechanistically, the deletion of Ptbp1 reduces the migration of endothelial cells, disrupting cardiomyocyte proliferation and ultimately leading to the LVNC. Further study shows that Ptbp1 deficiency changes the alternative splicing of ß-arrestin-1 (Arrb1), which affects endothelial cell migration. In conclusion, as an alternative splicing factor, PTBP1 is essential during ventricular chamber development, and its deficiency can lead to congenital heart disease.

Identification of an endogenous glutamatergic transmitter system controlling excitability and conductivity of atrial cardiomyocytes.

As an excitatory transmitter system, the glutamatergic transmitter system controls excitability and conductivity of neurons. Since both cardiomyocytes and neurons are excitable cells, we hypothesized that cardiomyocytes may also be regulated by a similar system. Here, we have demonstrated that atrial cardiomyocytes have an intrinsic glutamatergic transmitter system, which regulates the generation and propagation of action potentials. First, there are abundant vesicles containing glutamate beneath the plasma membrane of rat atrial cardiomyocytes. Second, rat atrial cardiomyocytes express key elements of the glutamatergic transmitter system, such as the glutamate metabolic enzyme, ionotropic glutamate receptors (iGluRs), and glutamate transporters. Third, iGluR agonists evoke iGluR-gated currents and decrease the threshold of electrical excitability in rat atrial cardiomyocytes. Fourth, iGluR antagonists strikingly attenuate the conduction velocity of electrical impulses in rat atrial myocardium both in vitro and in vivo. Knockdown of GRIA3 or GRIN1, two highly expressed iGluR subtypes in atria, drastically decreased the excitatory firing rate and slowed down the electrical conduction velocity in cultured human induced pluripotent stem cell (iPSC)-derived atrial cardiomyocyte monolayers. Finally, iGluR antagonists effectively prevent and terminate atrial fibrillation in a rat isolated heart model. In addition, the key elements of the glutamatergic transmitter system are also present and show electrophysiological functions in human atrial cardiomyocytes. In conclusion, our data reveal an intrinsic glutamatergic transmitter system directly modulating excitability and conductivity of atrial cardiomyocytes through controlling iGluR-gated currents. Manipulation of this system may open potential new avenues for therapeutic intervention of cardiac arrhythmias.