TRAIL-induced apoptosis in human vascular endothelium is regulated by phosphatidylinositol 3-kinase/Akt through the short form of cellular FLIP and Bcl-2

Salima J. Alladina, Jin H. Song, Sandra T. Davidge, Chunhai Hao, Alexander S. Easton

Research output: Contribution to journalArticle

55 Citations (Scopus)

Abstract

Background: Apoptosis of vascular endothelial cells plays a central role in angiogenesis and atherosclerosis. This study investigates the molecular mechanisms of endothelial apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) following inhibition of phosphatidylinositol 3-kinase (PI3K). It examines downstream regulation and activation of the extrinsic and intrinsic pathways. Methods and Results: By flow cytometry, TRAIL receptors 2 and 3 were present to a greater extent than receptors 1 and 4. TRAIL reduced cell numbers in combination with the PI3K inhibitor LY 294002. TRAIL (100 ng/ml) with LY 294002 (20 μmol/l) activated the extrinsic pathway, causing progressive cleavage of caspase-8 and caspase-3. Activation of the intrinsic pathway proceeded by release of mitochondrial factors Smac/DIABLO and cytochrome c, and caspase-9 cleavage. LY 294002 reduced phosphorylated Akt (p-Akt), with early loss of the short form of cellular FLIP (c-FLIPs) and concurrent reduction of Bcl-2. Treatment with small interfering RNA against PI3K also reduced c-FLIPs and Bcl-2, and cotreatment with TRAIL triggered caspase-3 cleavage. Conclusions: This study details the molecular regulation of TRAIL-induced apoptosis in vascular endothelium. Inhibition of PI3K reduces p-Akt, with concurrent reductions in c-FLIPs and Bcl-2, and so renders endothelium sensitive to TRAIL-induced apoptosis through the extrinsic and intrinsic pathways.

Original languageEnglish (US)
Pages (from-to)337-347
Number of pages11
JournalJournal of Vascular Research
Volume42
Issue number4
DOIs
StatePublished - Jul 1 2005
Externally publishedYes

Fingerprint

CASP8 and FADD-Like Apoptosis Regulating Protein
Phosphatidylinositol 3-Kinase
Vascular Endothelium
Apoptosis
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Caspase 3
Receptors, Tumor Necrosis Factor, Member 10c
TNF-Related Apoptosis-Inducing Ligand Receptors
Caspase 9
Caspase 8
Cytochromes c
Small Interfering RNA
Endothelium
Atherosclerosis
Flow Cytometry
Endothelial Cells
Tumor Necrosis Factor-alpha
Cell Count
Ligands

Keywords

  • Apoptosis
  • Endothelium
  • Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)

ASJC Scopus subject areas

  • Physiology

Cite this

TRAIL-induced apoptosis in human vascular endothelium is regulated by phosphatidylinositol 3-kinase/Akt through the short form of cellular FLIP and Bcl-2. / Alladina, Salima J.; Song, Jin H.; Davidge, Sandra T.; Hao, Chunhai; Easton, Alexander S.

In: Journal of Vascular Research, Vol. 42, No. 4, 01.07.2005, p. 337-347.

Research output: Contribution to journalArticle

@article{3ff9ecbe3cf0418fb35b8fdcd95f1a0f,
title = "TRAIL-induced apoptosis in human vascular endothelium is regulated by phosphatidylinositol 3-kinase/Akt through the short form of cellular FLIP and Bcl-2",
abstract = "Background: Apoptosis of vascular endothelial cells plays a central role in angiogenesis and atherosclerosis. This study investigates the molecular mechanisms of endothelial apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) following inhibition of phosphatidylinositol 3-kinase (PI3K). It examines downstream regulation and activation of the extrinsic and intrinsic pathways. Methods and Results: By flow cytometry, TRAIL receptors 2 and 3 were present to a greater extent than receptors 1 and 4. TRAIL reduced cell numbers in combination with the PI3K inhibitor LY 294002. TRAIL (100 ng/ml) with LY 294002 (20 μmol/l) activated the extrinsic pathway, causing progressive cleavage of caspase-8 and caspase-3. Activation of the intrinsic pathway proceeded by release of mitochondrial factors Smac/DIABLO and cytochrome c, and caspase-9 cleavage. LY 294002 reduced phosphorylated Akt (p-Akt), with early loss of the short form of cellular FLIP (c-FLIPs) and concurrent reduction of Bcl-2. Treatment with small interfering RNA against PI3K also reduced c-FLIPs and Bcl-2, and cotreatment with TRAIL triggered caspase-3 cleavage. Conclusions: This study details the molecular regulation of TRAIL-induced apoptosis in vascular endothelium. Inhibition of PI3K reduces p-Akt, with concurrent reductions in c-FLIPs and Bcl-2, and so renders endothelium sensitive to TRAIL-induced apoptosis through the extrinsic and intrinsic pathways.",
keywords = "Apoptosis, Endothelium, Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)",
author = "Alladina, {Salima J.} and Song, {Jin H.} and Davidge, {Sandra T.} and Chunhai Hao and Easton, {Alexander S.}",
year = "2005",
month = "7",
day = "1",
doi = "10.1159/000086599",
language = "English (US)",
volume = "42",
pages = "337--347",
journal = "Journal of Vascular Research",
issn = "1018-1172",
publisher = "S. Karger AG",
number = "4",

}

TY - JOUR

T1 - TRAIL-induced apoptosis in human vascular endothelium is regulated by phosphatidylinositol 3-kinase/Akt through the short form of cellular FLIP and Bcl-2

AU - Alladina, Salima J.

AU - Song, Jin H.

AU - Davidge, Sandra T.

AU - Hao, Chunhai

AU - Easton, Alexander S.

PY - 2005/7/1

Y1 - 2005/7/1

N2 - Background: Apoptosis of vascular endothelial cells plays a central role in angiogenesis and atherosclerosis. This study investigates the molecular mechanisms of endothelial apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) following inhibition of phosphatidylinositol 3-kinase (PI3K). It examines downstream regulation and activation of the extrinsic and intrinsic pathways. Methods and Results: By flow cytometry, TRAIL receptors 2 and 3 were present to a greater extent than receptors 1 and 4. TRAIL reduced cell numbers in combination with the PI3K inhibitor LY 294002. TRAIL (100 ng/ml) with LY 294002 (20 μmol/l) activated the extrinsic pathway, causing progressive cleavage of caspase-8 and caspase-3. Activation of the intrinsic pathway proceeded by release of mitochondrial factors Smac/DIABLO and cytochrome c, and caspase-9 cleavage. LY 294002 reduced phosphorylated Akt (p-Akt), with early loss of the short form of cellular FLIP (c-FLIPs) and concurrent reduction of Bcl-2. Treatment with small interfering RNA against PI3K also reduced c-FLIPs and Bcl-2, and cotreatment with TRAIL triggered caspase-3 cleavage. Conclusions: This study details the molecular regulation of TRAIL-induced apoptosis in vascular endothelium. Inhibition of PI3K reduces p-Akt, with concurrent reductions in c-FLIPs and Bcl-2, and so renders endothelium sensitive to TRAIL-induced apoptosis through the extrinsic and intrinsic pathways.

AB - Background: Apoptosis of vascular endothelial cells plays a central role in angiogenesis and atherosclerosis. This study investigates the molecular mechanisms of endothelial apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) following inhibition of phosphatidylinositol 3-kinase (PI3K). It examines downstream regulation and activation of the extrinsic and intrinsic pathways. Methods and Results: By flow cytometry, TRAIL receptors 2 and 3 were present to a greater extent than receptors 1 and 4. TRAIL reduced cell numbers in combination with the PI3K inhibitor LY 294002. TRAIL (100 ng/ml) with LY 294002 (20 μmol/l) activated the extrinsic pathway, causing progressive cleavage of caspase-8 and caspase-3. Activation of the intrinsic pathway proceeded by release of mitochondrial factors Smac/DIABLO and cytochrome c, and caspase-9 cleavage. LY 294002 reduced phosphorylated Akt (p-Akt), with early loss of the short form of cellular FLIP (c-FLIPs) and concurrent reduction of Bcl-2. Treatment with small interfering RNA against PI3K also reduced c-FLIPs and Bcl-2, and cotreatment with TRAIL triggered caspase-3 cleavage. Conclusions: This study details the molecular regulation of TRAIL-induced apoptosis in vascular endothelium. Inhibition of PI3K reduces p-Akt, with concurrent reductions in c-FLIPs and Bcl-2, and so renders endothelium sensitive to TRAIL-induced apoptosis through the extrinsic and intrinsic pathways.

KW - Apoptosis

KW - Endothelium

KW - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)

UR - http://www.scopus.com/inward/record.url?scp=23844464209&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=23844464209&partnerID=8YFLogxK

U2 - 10.1159/000086599

DO - 10.1159/000086599

M3 - Article

VL - 42

SP - 337

EP - 347

JO - Journal of Vascular Research

JF - Journal of Vascular Research

SN - 1018-1172

IS - 4

ER -