Different Effects of Species-dependent Funny Channel Current on Engineered Biological Pacemaking Activity

摘要

It has been verified that biological pacemaker could be produced based on ventricular myocytes (VMs) by overexpressing HCN gene which codes the expression of hyperpolarization-activated current (I_f). Clinically, xenograft is in common use by which one specie' stem cell is infected with another specie's HCN gene so that the stem cell could transfer into cardiac pacemaker cell. The difference of HCN gene between species affects I_f properties, but how the I_f properties influence pacemaker creation is not easy to be qualified in biological experiments. In this study, we build an engineered biological pacemaker model based on a ventricular myocyte model by incorporating I_f formulation and simulated the membrane potential of biological pacemaker. The I_f of different species is simulated by modifying average half-maximal activation voltage (V_1/2) of I_f activation gate and I_f conductance (G_f). Based on the modified pacemaker model, the effect of I_f properties on pacemaking stability and frequency is evaluated. Simulation results indicate that pacemaking ability is influenced dramatically by I_f properties. In addition, the spontaneous pacemaking mechanism showed both membrane-clock and Ca²⁺-clock and its deep reason is analyzed in this paper. This study may provide a subcellular perspective for the clinical use of biological pacemaker.