Hydrogen Sulfide Suppresses Outward Rectifier Potassium Currents in Human Pluripotent Stem Cell-Derived Cardiomyocytes

Abstract

AimHydrogen sulfide (H2S) is a promising cardioprotective agent and a potential modulator of cardiac ion currents. Yet its cardiac effects on humans are poorly understood due to lack of functional cardiomyocytes. This study investigates electrophysiological responses of human pluripotent stem cells (hPSCs) derived cardiomyocytes towards H2S.Methods and ResultsCardiomyocytes of ventricular, atrial and nodal subtypes differentiated from H9 embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs) were electrophysiologically characterized. The effect of NaHS, a donor of H2S, on action potential (AP), outward rectifier potassium currents (I Ks and I Kr), L-type Ca2+ currents (I CaL) and hyperpolarization-activated inward current (I f) were determined by patch-clamp electrophysiology and confocal calcium imaging. In a concentration-dependent manner, NaHS (100 to 300 µM) consistently altered the action potential properties including prolonging action potential duration (APD) and slowing down contracting rates of ventricular-and atrial-like cardiomyocytes derived from both hESCs and hiPSCs. Moreover, inhibitions of slow and rapid I K (I Ks and I Kr), I CaL and I f were found in NaHS treated cardiomyocytes and it could collectively contribute to the remodeling of AP properties.ConclusionsThis is the first demonstration of effects of H2S on cardiac electrophysiology of human ventricular-like, atrial-like and nodal-like cardiomyocytes. It reaffirmed the inhibitory effect of H2S on I CaL and revealed additional novel inhibitory effects on I f, I Ks and I Kr currents in human cardiomyocytes.

Cardiomyocyte differentiation of pluripotent stem cells with SB203580 analogues correlates with Wnt pathway CK1 inhibition independent of p38 MAPK signaling

“…Whole cell patch clamp recording was performed with an Axon 200B patch clamp amplifier (Axon instrument, Union City, USA) and a Digidata 1440A digitizer [19]. Data was low-pass filtered at 2 kHz and sampled at 1 kHz.…”

Hydrogen sulfide inhibits Kir2 and Kir3 channels by decreasing sensitivity to the phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2)

“…H 2 S mediates ischemic damage pursuant to stroke in neuronal tissue (15), whereas it serves as a powerful cardioprotective agent upon comparable conditions. One categorical correlation that emerged in the studies highlighting this 'dual physiological effect' by the gaseous mediator is that while H 2 S depolarizes cerebral components (8)(9)(10)(11)(12), it hyperpolarizes cardiomyocytes (13,14). In other words, H 2 S increases the excitability of cerebral tissue, worsening seizure-like symptoms and rendering neurons more susceptible to ischemic insult (12,15).…”

“…Collectively, H 2 S has been shown to play a role in diverse physiological processes, such as cellular necrosis, apoptosis, oxidative stress, or inflammation (7). One theme emerging from these studies is that H 2 S increases the excitability of neuronal compartments (8-12), whereas it depresses excitability of cardiac tissues (13,14), correlating to neurotoxic (12,15) and cardioprotective (16)(17)(18)(19)(20) effects, respectively. Therefore, exactly how H 2 S is affecting differentially ion channels expressed in cells that rapidly control membrane excitability has become a central question.…”

Evaluation of the Cardiotoxicity of Mitragynine and Its Analogues Using Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes

“… [19] hiPSC-CMs have ionic currents characteristics resembling those reported for adult human cardiomyocytes. [20] , [21] They have been successfully adopted in disease modeling of long QT syndrome (LQTS) and drug testing [22] .…”