Role of glucosylceramide in lung endothelial cell fate and emphysema

Kengo Koike, Evgeny V. Berdyshev, Andrew M. Mikosz, Irina A. Bronova, Anna S. Bronoff, John P. Jung, Erica L. Beatman, Kevin Ni, Danting Cao, April K. Scruggs, Karina A. Serban, Irina Petrache

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Rationale: The loss of pulmonary endothelial cells in emphysema is associated with increased lung ceramide. Ceramide perturbations may cause adaptive alterations in other bioactive sphingolipids, with pathogenic implications. We previously reported a negative correlation between emphysema and circulating glycosphingolipids (GSLs). Glucosylceramide (GlcCer), the initial GSL synthesized from ceramide by GCS (GlcCer synthase), is required for embryonic survival, but its role in the lung is unknown. Objectives: To determine if cigarette smoke (CS) alters lung GlcCer and to elucidate the role of GCS in lung endothelial cell fate. Methods: GlcCer was measured by tandem mass spectrometry in BAL fluid of CS- or elastase-exposed mice, and GCS was detected by Western blotting in chronic obstructive pulmonary disease lungs and CS extract-exposed primary human lungmicrovascular endothelial cells (HLMVECs). The role of GlcCer and GCS on mTOR (mammalian target of rapamycin) signaling, autophagy, lysosomal function, and cell death were studied in HLMVECs with or without CS exposure. Measurements and Main Results: Mice exposed to chronic CS or to elastase, and patients with chronic obstructive pulmonary disease, exhibited significantly decreased lung GlcCer and GCS. In mice, lung GlcCer levels were negatively correlated with airspace size. GCS inhibition in HLMVEC increased lysosomal pH, suppressed mTOR signaling, and triggered autophagy with impaired lysosomal degradation and apoptosis, recapitulating CS effects. In turn, increasing GlcCer by GCS overexpression in HLMVEC improved autophagic flux and attenuated CS-induced apoptosis. Conclusions: Decreased GSL production in response to CS may be involved in emphysema pathogenesis, associated with autophagy with impaired lysosomal degradation and lung endothelial cell apoptosis.

Original languageEnglish (US)
Pages (from-to)1113-1125
Number of pages13
JournalAmerican journal of respiratory and critical care medicine
Volume200
Issue number9
DOIs
StatePublished - Nov 1 2019
Externally publishedYes

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ceramide glucosyltransferase
Glucosylceramides
Emphysema
Endothelial Cells
Smoke
Tobacco Products
Lung
Glycosphingolipids
Autophagy
Ceramides
Pancreatic Elastase
Sirolimus
Apoptosis
Chronic Obstructive Pulmonary Disease
Dimercaprol
Sphingolipids

Keywords

  • Apoptosis
  • Autophagy
  • Chronic obstructive pulmonary disease
  • Endothelium
  • Sphingolipids

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

Cite this

Role of glucosylceramide in lung endothelial cell fate and emphysema. / Koike, Kengo; Berdyshev, Evgeny V.; Mikosz, Andrew M.; Bronova, Irina A.; Bronoff, Anna S.; Jung, John P.; Beatman, Erica L.; Ni, Kevin; Cao, Danting; Scruggs, April K.; Serban, Karina A.; Petrache, Irina.

In: American journal of respiratory and critical care medicine, Vol. 200, No. 9, 01.11.2019, p. 1113-1125.

Research output: Contribution to journalArticle

Koike, K, Berdyshev, EV, Mikosz, AM, Bronova, IA, Bronoff, AS, Jung, JP, Beatman, EL, Ni, K, Cao, D, Scruggs, AK, Serban, KA & Petrache, I 2019, 'Role of glucosylceramide in lung endothelial cell fate and emphysema', American journal of respiratory and critical care medicine, vol. 200, no. 9, pp. 1113-1125. https://doi.org/10.1164/rccm.201812-2311OC
Koike, Kengo ; Berdyshev, Evgeny V. ; Mikosz, Andrew M. ; Bronova, Irina A. ; Bronoff, Anna S. ; Jung, John P. ; Beatman, Erica L. ; Ni, Kevin ; Cao, Danting ; Scruggs, April K. ; Serban, Karina A. ; Petrache, Irina. / Role of glucosylceramide in lung endothelial cell fate and emphysema. In: American journal of respiratory and critical care medicine. 2019 ; Vol. 200, No. 9. pp. 1113-1125.
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abstract = "Rationale: The loss of pulmonary endothelial cells in emphysema is associated with increased lung ceramide. Ceramide perturbations may cause adaptive alterations in other bioactive sphingolipids, with pathogenic implications. We previously reported a negative correlation between emphysema and circulating glycosphingolipids (GSLs). Glucosylceramide (GlcCer), the initial GSL synthesized from ceramide by GCS (GlcCer synthase), is required for embryonic survival, but its role in the lung is unknown. Objectives: To determine if cigarette smoke (CS) alters lung GlcCer and to elucidate the role of GCS in lung endothelial cell fate. Methods: GlcCer was measured by tandem mass spectrometry in BAL fluid of CS- or elastase-exposed mice, and GCS was detected by Western blotting in chronic obstructive pulmonary disease lungs and CS extract-exposed primary human lungmicrovascular endothelial cells (HLMVECs). The role of GlcCer and GCS on mTOR (mammalian target of rapamycin) signaling, autophagy, lysosomal function, and cell death were studied in HLMVECs with or without CS exposure. Measurements and Main Results: Mice exposed to chronic CS or to elastase, and patients with chronic obstructive pulmonary disease, exhibited significantly decreased lung GlcCer and GCS. In mice, lung GlcCer levels were negatively correlated with airspace size. GCS inhibition in HLMVEC increased lysosomal pH, suppressed mTOR signaling, and triggered autophagy with impaired lysosomal degradation and apoptosis, recapitulating CS effects. In turn, increasing GlcCer by GCS overexpression in HLMVEC improved autophagic flux and attenuated CS-induced apoptosis. Conclusions: Decreased GSL production in response to CS may be involved in emphysema pathogenesis, associated with autophagy with impaired lysosomal degradation and lung endothelial cell apoptosis.",
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AU - Berdyshev, Evgeny V.

AU - Mikosz, Andrew M.

AU - Bronova, Irina A.

AU - Bronoff, Anna S.

AU - Jung, John P.

AU - Beatman, Erica L.

AU - Ni, Kevin

AU - Cao, Danting

AU - Scruggs, April K.

AU - Serban, Karina A.

AU - Petrache, Irina

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KW - Autophagy

KW - Chronic obstructive pulmonary disease

KW - Endothelium

KW - Sphingolipids

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