T-cadherin protects endothelial cells from oxidative stress-induced apoptosis

FASEB J. 2005 Oct;19(12):1737-9. doi: 10.1096/fj.05-3834fje. Epub 2005 Aug 12.

Abstract

In vascular tissue, T-cadherin (T-cad) is up-regulated in vivo under disease conditions associated with oxidative stress and concomitant cell migration, proliferation and apoptosis/survival. Using cultures of human umbilical vein endothelial cells (HUVEC), we examined whether there is a functional relationship between oxidative stress, T-cad expression, and cell survival status. Culture of HUVEC under conditions of oxidative stress (e.g., serum deprivation, inclusion of H2O2) resulted in increased T-cad expression. Oxidative stress-induced increases in T-cad were inhibited by the free radical-scavenging antioxidant, N-acetylcysteine, and the flavin-containing oxidase inhibitor, diphenyleneiodonium. Thus reactive oxygen species (ROS) contribute to stress-induced elevation of T-cad in HUVEC. Compared with control cells, HUVEC overexpressing T-cad (T-cad+-HUVEC) had higher phosphorylation levels for phosphatidylinositol 3-kinase (PI3K) target Akt and mTOR target p70(S6K) (survival pathway regulators), but lower levels for p38MAPK (death pathway regulator). T-cad+-HUVEC exposed to stress (serum-deprivation, TNF-alpha, actinomycin D, staurosporine) exhibited reduced caspase activation together with increased cell survival. Protection against stress-induced apoptosis in T-cad+-HUVEC was abrogated by either PI3K-inhibitor wortmannin or mTOR-inhibitor rapamycin. We conclude that T-cad overexpression in HUVEC protects against stress-induced apoptosis through activation of the PI3K/Akt/mTOR survival signal pathway and concomitant suppression of the p38 MAPK proapoptotic pathway. ROS-induced changes in T-cad expression may play an important role in controlling tissue cellularity during vascular remodeling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics
  • Androstadienes / pharmacology
  • Apoptosis*
  • Cadherins / chemistry
  • Cadherins / physiology*
  • Caspases / metabolism
  • Cell Survival
  • Cells, Cultured
  • Dactinomycin / pharmacology
  • Endothelial Cells / cytology
  • Endothelium, Vascular / cytology*
  • Enzyme Activation
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Immunoblotting
  • Immunohistochemistry
  • Immunosuppressive Agents / pharmacology
  • MAP Kinase Signaling System
  • Microscopy, Fluorescence
  • Models, Biological
  • Nucleic Acid Synthesis Inhibitors / pharmacology
  • Oxidative Stress*
  • Reactive Oxygen Species / metabolism
  • Signal Transduction
  • Sirolimus / pharmacology
  • Staurosporine / pharmacology
  • Time Factors
  • Tumor Necrosis Factor-alpha / metabolism
  • Wortmannin
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Androstadienes
  • Cadherins
  • Enzyme Inhibitors
  • H-cadherin
  • Immunosuppressive Agents
  • Nucleic Acid Synthesis Inhibitors
  • Reactive Oxygen Species
  • Tumor Necrosis Factor-alpha
  • Dactinomycin
  • p38 Mitogen-Activated Protein Kinases
  • Caspases
  • Staurosporine
  • Sirolimus
  • Wortmannin