Carbon monoxide differentially modulates STAT1 and STAT3 and inhibits apoptosis via a phosphatidylinositol 3-kinase/Akt and p38 kinase-dependent STAT3 pathway during anoxia-reoxygenation injury

Xuchen Zhang, Peiying Shan, Jawed Alam, Xin Yuan Fu, Patty J. Lee

Research output: Contribution to journalArticle

163 Citations (Scopus)

Abstract

Carbon monoxide (CO), previously considered a toxic waste product of heme catabolism, is emerging as an important gaseous molecule. In addition to its important role in neurotransmission, exogenous CO protects against vascular injury, transplant rejection, and acute lung injury. However, little is known regarding the precise signaling mechanisms of CO. We have recently shown that CO attenuates endothelial cell apoptosis during anoxia-reoxygenation injury by activating MKK3/p38α mitogen-activated protein kinase (MAPK) pathways. Our current study is the first to demonstrate that CO can differentially modulate STAT1 and STAT3 activation and, specifically, that STAT3 activation by CO is responsible for the anti-apoptotic effect in endothelial cells. In addition, we show that the anti-apoptotic effects of CO depend upon both phosphatidylinositol 3-kinase/Akt and p38 MAPK signaling pathways in endothelial cells, whereas previous reports have implicated only the MKK3/p38 MAPK pathway. Using chemical inhibitors and dominant negative constructs, we show that CO enhances STAT3 activation via phosphatidylinositol 3-kinase/Akt and p38 MAPK pathways with subsequent attenuation of Fas expression and caspase 3 activity. These data highlight the anti-apoptotic signaling mechanisms of CO and, importantly, delineate potential therapeutic strategies to prevent ischemia-reperfusion or anoxia-reoxygenation injury in the vasculature.

Original languageEnglish
Pages (from-to)8714-8721
Number of pages8
JournalJournal of Biological Chemistry
Volume280
Issue number10
DOIs
StatePublished - Mar 11 2005

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Phosphatidylinositol 3-Kinase
Carbon Monoxide
Phosphotransferases
Apoptosis
Wounds and Injuries
p38 Mitogen-Activated Protein Kinases
Endothelial cells
Endothelial Cells
Chemical activation
Waste Products
Toxic materials
Hypoxia
Transplants
Acute Lung Injury
Poisons
Vascular System Injuries
Graft Rejection
Heme
Synaptic Transmission
Caspase 3

ASJC Scopus subject areas

  • Biochemistry

Cite this

Carbon monoxide differentially modulates STAT1 and STAT3 and inhibits apoptosis via a phosphatidylinositol 3-kinase/Akt and p38 kinase-dependent STAT3 pathway during anoxia-reoxygenation injury. / Zhang, Xuchen; Shan, Peiying; Alam, Jawed; Fu, Xin Yuan; Lee, Patty J.

In: Journal of Biological Chemistry, Vol. 280, No. 10, 11.03.2005, p. 8714-8721.

Research output: Contribution to journalArticle

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