Particulate matter 2.5 induced arrhythmogenesis mediated by TRPC3 in human induced pluripotent stem cell-derived cardiomyocytes

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Abstract

Particulate matter (PM) is one of the most important environmental issues worldwide, which is associated with not only pulmonary but also cardiovascular diseases. However, the underlying biological mechanisms of PM related cardiovascular dysfunction remained poorly defined, especially mediated by the pathway of direct impact on vascular and heart. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) provide an ideal platform for studying PM-exposed cellular diseases model in vitro. Here, we investigated the direct effects of particulate matter 2.5 (PM2.5) on hiPSC-CMs and the potential mechanism at non-cytotoxic concentrations. Cell viability, contraction amplitude and spontaneous beating rate of iPSC-CMs after direct exposure to PM2.5 showed that the concentration of lower than 100 µg/ml would not lead to cytotoxic effects. Calcium-mediated optical mapping illustrated that there was a concentration-dependent reduction in quantification of calcium transient amplitude and an increase in the incidence of early after depolarizations due to PM2.5 treatment. Furthermore, there were dramatic dosage-dependent shortening in action potential duration and decrease in L-type calcium peak current density. The Ingenuity Pathway Analysis of our transcriptive study indicated that PM2.5 exposure preferentially influenced the expression of genes involved in calcium signaling. Among them the up-regulation of TRPC3 potentially played an important role in the electrophysiological alteration of PM2.5 on hiPSC-CMs, which could be ameliorated by pretreatment with pyr3, the inhibitor of TRPC3. In conclusion, our results demonstrated that exposure to PM2.5 was capable of increasing propensity to cardiac arrhythmias which could be attenuated with TRPC3 inhibition.

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Change history

  • 06 September 2019

    During the course of writing and revision of this paper, the authorship changed. Min Ling, M.S. and Quian Bian, Ph.D., are added in the list of authors.

Abbreviations

PM:

Particulate matter

CVD:

Cardiovascular disease

PM2.5:

Particulate matter 2.5

hiPSC:

Human induced pluripotent stem cell

hiPSC-CMs:

Human induced pluripotent stem cell-derived cardiomyocytes

PBS:

Phosphate-buffered saline

CCK-8:

Cell counting kit

CE96:

CardioExcyte 96

cTnI:

Cardiac troponin-I

EAD:

Early afterdepolarization

AP:

Action potential

RT-PCR:

Real-time polymerase chain reaction

APD:

Action potential duration

IPA:

Ingenuity pathway analysis

DEP:

Diesel exhaust particulate

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Correspondence to Jiaxian Wang or Minglong Chen.

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Cai, C., Huang, J., Lin, Y. et al. Particulate matter 2.5 induced arrhythmogenesis mediated by TRPC3 in human induced pluripotent stem cell-derived cardiomyocytes. Arch Toxicol 93, 1009–1020 (2019). https://doi.org/10.1007/s00204-019-02403-y

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Keywords

  • Particulate matter
  • Human induced pluripotent stem cells
  • Cardiomyocytes
  • Electrophysiology
  • TRPC3