Nitric oxide-enhanced caspase-3 and acidic sphingomyelinase interaction: A novel mechanism by which airway epithelial cells escape ceramide-induced apoptosis

S. Sianna Castillo, Michal Levy, Chunbo Wang, Jyoti V. Thaikoottathil, Elaine Khan, Tzipora Goldkorn

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

Reactive nitrogen species (RNS) are implicated in the pathophysiology of inflammatory lung diseases such as asthma and chronic obstructive pulmonary disease. The molecular mechanisms and signaling events involved in lung cell injury by RNS are still poorly understood. In the current study, we observe a novel anti-apoptotic response to nitric oxide (NO) exposure (via the NO donors 3-morpholine-syndnonimine (SIN1) or papa-NONOate) of human airway epithelial (HAE) cells. NO exposure via the NO donors increased cellular ceramide levels via ceramide synthase but did not trigger an apoptotic response. Rather, exposure to the NO donors promoted an increase in the protein-protein interaction between acidic sphingomyelinase (aSMase) and caspase-3, with aSMase sequestering caspase-3 and preventing its cleavage. In contrast, when aSMase was silenced in HAE cells or was knocked out in mice, an increase in cleaved caspase-3 was observed. This elevated caspase-3 cleavage was further augmented upon NO exposure (via SIN1 or papa-NONOate) of HAE cells and could be prevented by an inhibitor to ceramide synthase. These results demonstrate a novel mechanism of NO modulation of apoptosis, in which HAE cells exposed to NO via an NO donor induces ceramide generation via ceramide synthase. However, this ceramide induction does not lead to apoptosis unless aSMase is knocked down, allowing the release of caspase-3, its activation and execution of apoptosis.

Original languageEnglish (US)
Pages (from-to)816-823
Number of pages8
JournalExperimental Cell Research
Volume313
Issue number4
DOIs
StatePublished - Feb 15 2007

Fingerprint

Sphingomyelin Phosphodiesterase
Ceramides
Caspase 3
Nitric Oxide Donors
Nitric Oxide
Epithelial Cells
Apoptosis
Reactive Nitrogen Species
Lung Injury
Chronic Obstructive Pulmonary Disease
Lung Diseases
Proteins
Asthma
dihydroceramide desaturase

Keywords

  • Acidic sphingomyelinase
  • Apoptosis
  • Ceramide
  • Nitric oxide

ASJC Scopus subject areas

  • Cell Biology

Cite this

Nitric oxide-enhanced caspase-3 and acidic sphingomyelinase interaction : A novel mechanism by which airway epithelial cells escape ceramide-induced apoptosis. / Castillo, S. Sianna; Levy, Michal; Wang, Chunbo; Thaikoottathil, Jyoti V.; Khan, Elaine; Goldkorn, Tzipora.

In: Experimental Cell Research, Vol. 313, No. 4, 15.02.2007, p. 816-823.

Research output: Contribution to journalArticle

Castillo, S. Sianna ; Levy, Michal ; Wang, Chunbo ; Thaikoottathil, Jyoti V. ; Khan, Elaine ; Goldkorn, Tzipora. / Nitric oxide-enhanced caspase-3 and acidic sphingomyelinase interaction : A novel mechanism by which airway epithelial cells escape ceramide-induced apoptosis. In: Experimental Cell Research. 2007 ; Vol. 313, No. 4. pp. 816-823.
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