T-cadherin protects endothelial cells from oxidative stress-induced apoptosis.
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.
Joshi
Manjunath B
MB
Department of Research, Cardiovascular Laboratories, Basel University Hospital, Basel, Switzerland.
Philippova
Maria
M
Ivanov
Danila
D
Allenspach
Roy
R
Erne
Paul
P
Resink
Thérèse J
TJ
D000256:Adenoviridae / Q000235:genetics; D000730:Androstadienes / Q000494:pharmacology; D017209:Apoptosis; D015820:Cadherins / Q000737:chemistry / Q000502:physiology*; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival; D002478:Cells, Cultured; D003609:Dactinomycin / Q000494:pharmacology; D042783:Endothelial Cells / Q000166:cytology; D004730:Endothelium, Vascular / Q000166:cytology*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D019311:Staurosporine / Q000494:pharmacology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000077191:Wortmannin; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000730:Androstadienes; D015820:Cadherins; D004791:Enzyme Inhibitors; C099972:H-cadherin; D007166:Immunosuppressive Agents; D019384:Nucleic Acid Synthesis Inhibitors; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D003609:Dactinomycin; D048051:p38 Mitogen-Activated Protein Kinases; D020169:Caspases; D019311:Staurosporine; D020123:Sirolimus; D000077191:Wortmannin