CD36 mediates H2O2-induced calcium influx in lung microvascular endothelial cells

Karthik Suresh, Laura Servinsky, Jose Reyes, Clark Undem, Joel Zaldumbide, Otgonchimeg Rentsendorj, Sruti Modekurty, Jeffrey M Dodd-o, Alan Leroy Scott, David B Pearse, Larissa Shimoda

Research output: Contribution to journalArticle

Abstract

Elevated levels of reactive oxygen species and intracellular Ca2+play a key role in endothelial barrier dysfunction in acute lung injury. We previously showed that H2O2- induced increases in intracellular calcium concentrations ([Ca2+]i) in lung microvascular endothelial cells (LMVECs) involve the membrane Ca2+channel, transient receptor potential vanilloid-4 (TRPV4) and that inhibiting this channel attenuated H2O2-induced barrier disruption in vitro. We also showed that phosphorylation of TRPV4 by the Src family kinase, Fyn, contributes to H2O2-induced Ca2+influx in LMVEC. In endothelial cells, Fyn is tethered to the cell membrane by CD36, a fatty acid transporter. In this study, we assessed the effect of genetic loss or pharmacological inhibition of CD36 on Ca2+responses to H2O2. H2O2-induced Ca2+influx was attenuated in LMVEC isolated from mice lacking CD36 (CD36_/_). TRPV4 expression and function was unchanged in LMVEC isolated from wild-type (WT) and CD36_/_mice, as well as mice with deficiency for Fyn (Fyn_/_). TRPV4 immunoprecipitated with Fyn, but this interaction was decreased in CD36_/_LMVEC. The amount of phosphorylated TRPV4 was decreased in LMVEC from CD36_/_mice compared with WT controls. Loss of CD36 altered subcellular localization of Fyn, while inhibition of CD36 fatty acid transport with succinimidyl oleate did not attenuate H2O2-induced Ca2+influx. Lastly, we found that CD36_/_mice were protected from ischemiareperfusion injury in vivo. In conclusion, our data suggest that CD36 plays an important role in H2O2-mediated lung injury and that the mechanism may involve CD36-dependent scaffolding of Fyn to the cell membrane to facilitate TRPV4 phosphorylation.

Original languageEnglish (US)
Pages (from-to)L143-L153
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume312
Issue number1
DOIs
StatePublished - Dec 2 2016

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TRPV Cation Channels
Endothelial Cells
Calcium
Lung
Cell Membrane
Phosphorylation
CD36 Antigens
src-Family Kinases
Acute Lung Injury
Lung Injury
Oleic Acid
Ion Channels
Reactive Oxygen Species
Fatty Acids
Pharmacology
Wounds and Injuries

Keywords

  • Acute lung injury
  • Calcium
  • ROS

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Cell Biology
  • Physiology (medical)

Cite this

CD36 mediates H2O2-induced calcium influx in lung microvascular endothelial cells. / Suresh, Karthik; Servinsky, Laura; Reyes, Jose; Undem, Clark; Zaldumbide, Joel; Rentsendorj, Otgonchimeg; Modekurty, Sruti; Dodd-o, Jeffrey M; Scott, Alan Leroy; Pearse, David B; Shimoda, Larissa.

In: American Journal of Physiology - Lung Cellular and Molecular Physiology, Vol. 312, No. 1, 02.12.2016, p. L143-L153.

Research output: Contribution to journalArticle

Suresh, Karthik ; Servinsky, Laura ; Reyes, Jose ; Undem, Clark ; Zaldumbide, Joel ; Rentsendorj, Otgonchimeg ; Modekurty, Sruti ; Dodd-o, Jeffrey M ; Scott, Alan Leroy ; Pearse, David B ; Shimoda, Larissa. / CD36 mediates H2O2-induced calcium influx in lung microvascular endothelial cells. In: American Journal of Physiology - Lung Cellular and Molecular Physiology. 2016 ; Vol. 312, No. 1. pp. L143-L153.
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AU - Undem, Clark

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AU - Rentsendorj, Otgonchimeg

AU - Modekurty, Sruti

AU - Dodd-o, Jeffrey M

AU - Scott, Alan Leroy

AU - Pearse, David B

AU - Shimoda, Larissa

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