Suppressing PTEN activity by tobacco smoke plus interleukin-1beta modulates dissociation of VE-cadherin/beta-catenin complexes in endothelium.
OBJECTIVE
Tobacco smoke (TS) interacts with inflammatory cytokines to produce endothelial dysfunction. We hypothesized that interleukin-1beta (IL-1beta) plus TS (TS/IL-1beta) induces disassembly of endothelial junctional complexes of VE-cadherin/beta-catenin by suppression of PTEN activity and investigated molecular mechanisms that modulate PTEN-deactivation in this situation.


RESULTS
TS/IL-1beta exposure, which disrupted adherens junctions and induced nuclear beta-catenin accumulation, increased tyrosine phosphorylation (p-Tyr) of VE-cadherin and beta-catenin, and reduced PTEN activity. Overexpression or silencing of PTEN modulated p-Tyr of both VE-cadherin and beta-catenin, changed assembly of adherens junction complexes, and altered nuclear beta-catenin accumulation. In addition, inhibiting ROS production stimulated by TS/IL-1beta decreased activation of Src, EGFR and p38MAPK, phosphorylation of PTEN, VE-cadherin and beta-catenin, and abrogated the effect of TS/IL-1beta to disorganize adherens junctions, resulting in reduced endothelial permeability and decreased nuclear beta-catenin accumulation. Finally, exposure of ApoE(-/-) mice to cigarette smoke-induced phosphorylation of Src, EGFR, p-38MAPK, PTEN, and beta-catenin, and disrupted VE-cadherin/beta-catenin complexes in cardiovascular tissue.


CONCLUSIONS
TS interaction with IL-1beta modulates PTEN activity though the ROS/Src/EGFR-p38MAPK pathway. PTEN deactivation is essential to increase VE-cadherin and beta-catenin p-Tyr and to disassemble VE-cadherin/beta-catenin membrane complexes, events that lead to accumulation of beta-catenin within the nucleus.
Barbieri
Silvia S
SS
Department of Pharmacological Sciences, University of Milan, Italy.
Ruggiero
Luca
L
Tremoli
Elena
E
Weksler
Babette B
BB
D022005:Adherens Junctions / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000737:chemistry / Q000378:metabolism*; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000209:etiology / Q000378:metabolism; D015820:Cadherins / Q000737:chemistry / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism*; D053583:Interleukin-1beta / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors*; D012906:Smoke / Q000009:adverse effects*; D012907:Smoking / Q000009:adverse effects; D051176:beta Catenin / Q000737:chemistry / Q000378:metabolism*; D000099152:Cadherin 5
D015703:Antigens, CD; D001057:Apolipoproteins E; D015820:Cadherins; D053583:Interleukin-1beta; D046912:Multiprotein Complexes; D051059:PTEN Phosphohydrolase; D012906:Smoke; D051176:beta Catenin; D000099152:Cadherin 5; C495267:CTNNB1 protein, mouse; C487757:Pten protein, mouse