E-cigarettes Induce Dysregulation of Autophagy Leading to Endothelial Dysfunction in Pulmonary Arterial Hypertension

Chen Wei Liu, Hoai Huong Thi Le, Philip Denaro, Zhiyu Dai, Ning Yi Shao, Sang Ging Ong, Won Hee Lee

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Given the increasing popularity of electronic cigarettes (e-cigs), it is imperative to evaluate the potential health risks of e-cigs, especially in users with preexisting health concerns such as pulmonary arterial hypertension (PAH). The aim of the present study was to investigate whether differential susceptibility exists between healthy and patients with PAH to e-cig exposure and the molecular mechanisms contributing to it. Patient-specific induced pluripotent stem cell-derived endothelial cells (iPSC-ECs) from healthy individuals and patients with PAH were used to investigate whether e-cig contributes to the pathophysiology of PAH and affects EC homeostasis in PAH. Our results showed that PAH iPSC-ECs showed a greater amount of damage than healthy iPSC-ECs upon e-cig exposure. Transcriptomic analyses revealed that differential expression of Akt3 may be responsible for increased autophagic flux impairment in PAH iPSC-ECs, which underlies increased susceptibility upon e-cig exposure. Moreover, knockdown of Akt3 in healthy iPSC-ECs significantly induced autophagic flux impairment and endothelial dysfunction, which further increased with e-cig treatment, thus mimicking the PAH cell phenotype after e-cig exposure. In addition, functional disruption of mTORC2 by knocking down Rictor in PAH iPSC-ECs caused autophagic flux impairment, which was mediated by downregulation of Akt3. Finally, pharmacological induction of autophagy via direct inhibition of mTORC1 and indirect activation of mTORC2 with rapamycin reverses e-cig-induced decreased Akt3 expression, endothelial dysfunction, autophagic flux impairment, and decreased cell viability, and migration in PAH iPSC-ECs. Taken together, these data suggest a potential link between autophagy and Akt3-mediated increased susceptibility to e-cig in PAH.

Original languageEnglish (US)
Pages (from-to)328-340
Number of pages13
JournalStem Cells
Volume41
Issue number4
DOIs
StatePublished - Apr 2023
Externally publishedYes

Keywords

  • Akt3
  • autophagic flux
  • e-cigarettes
  • endothelial dysfunction
  • human induced pluripotent stem cell-derived endothelial cells
  • pulmonary arterial hypertension

ASJC Scopus subject areas

  • General Medicine

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