Smoking exposure induces human lung endothelial cell adaptation to apoptotic stress

Daniela Petrusca, Mary Van Demark, Yuan Gu, Matthew J. Justice, Adriana Rogozea, Walter C. Hubbard, Irina Petrache

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Prolonged exposure to cigarette smoking is the main risk factor for emphysema, a component of chronic obstructive pulmonary diseases (COPDs) characterized by destruction of alveolar walls. Moreover, smoking is associated with pulmonary artery remodeling and pulmonary hypertension, even in the absence of COPD, through as yet unexplained mechanisms. In murine models, elevations of intraand paracellular ceramides in response to smoking have been implicated in the induction of lung endothelial cell apoptosis, but the role of ceramides in human cell counterparts is yet unknown. We modeled paracrine increases (outside-in) of palmitoyl ceramide (Cer16) in primary human lung microvascular cells. In naive cells, isolated from nonsmokers, Cer16 significantly reduced cellular proliferation and induced caspase-independent apoptosis via mitochondrial membrane depolarization, apoptosis-inducing factor translocation, and poly(ADP-ribose) polymerase cleavage. In these cells, caspase-3 was inhibited by ceramide-induced Akt phosphorylation, and by the induction of autophagic microtubule-associated protein-1 light-chain × lipidation. In contrast, cells isolated from smokers exhibited increased baseline proliferative features associated with lack of p16INK4a expression and Akt hyperphosphorylation. These cells were resistant to Cer16-induced apoptosis, despite presence of both endoplasmic reticulum stress response and mitochondrial membrane depolarization. In cells from smokers, the prominent up-regulation ofAkt pathways inhibited ceramide-triggered apoptosis, and was associated with elevated sphingosine and high-mobility group box 1, skewing the cell's response toward autophagy and survival. In conclusion, the cell responses to ceramide are modulated by an intricate cross-talk between Akt signaling and sphingolipid metabolites, and profoundly modified by previous cigarette smoke exposure, which selects for an apoptosis-resistant phenotype.

Original languageEnglish
Pages (from-to)513-525
Number of pages13
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Volume50
Issue number3
DOIs
StatePublished - 2014

Fingerprint

Ceramides
Endothelial cells
Endothelial Cells
Smoking
Lung
Apoptosis
Pulmonary diseases
Depolarization
Tobacco Products
Mitochondrial Membranes
Apoptosis Inducing Factor
Membranes
Chronic Obstructive Pulmonary Disease
Sphingolipids
Phosphorylation
Sphingosine
Microtubule-Associated Proteins
Poly(ADP-ribose) Polymerases
Caspases
Metabolites

Keywords

  • Apoptosis
  • Autophagy
  • Chronic obstructive pulmonary disease
  • High-mobility group box 1
  • Sphingolipids

ASJC Scopus subject areas

  • Cell Biology
  • Pulmonary and Respiratory Medicine
  • Molecular Biology
  • Clinical Biochemistry

Cite this

Smoking exposure induces human lung endothelial cell adaptation to apoptotic stress. / Petrusca, Daniela; Van Demark, Mary; Gu, Yuan; Justice, Matthew J.; Rogozea, Adriana; Hubbard, Walter C.; Petrache, Irina.

In: American Journal of Respiratory Cell and Molecular Biology, Vol. 50, No. 3, 2014, p. 513-525.

Research output: Contribution to journalArticle

Petrusca, Daniela ; Van Demark, Mary ; Gu, Yuan ; Justice, Matthew J. ; Rogozea, Adriana ; Hubbard, Walter C. ; Petrache, Irina. / Smoking exposure induces human lung endothelial cell adaptation to apoptotic stress. In: American Journal of Respiratory Cell and Molecular Biology. 2014 ; Vol. 50, No. 3. pp. 513-525.
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