The Journal of Heart and Lung Transplantation
Volume 27, Issue 12 , Pages 1311-1318, December 2008

Proliferation Signal Inhibitor–induced Decrease of Vascular Endothelial Cadherin Expression and Increase of Endothelial Permeability In Vitro Are Prevented by an Anti-oxidant

Department of Cardiology, Heart Transplant Research Laboratory, Swiss Cardiovascular Center Bern, University Hospital Bern (Inselspital), Bern, Switzerland

Received 24 April 2008; received in revised form 19 August 2008; accepted 26 August 2008.

Background

Rapamycins, sirolimus (SRL) and everolimus (ERL), are proliferation signal inhibitors (PSIs). PSI therapy often leads to edema. We hypothesized that increased oxidative stress in response to PSIs may modulate the expression of vascular endothelial (VE)-cadherin on endothelial cells (ECs) and, subsequently, vascular permeability, which in turn may be involved in the development of edema.

Methods

Experiments were performed on human umbilical vein ECs (HUVECs). Oxidative stress was measured by dichlorofluorescein-diacetate. Expression of VE-cadherin was evaluated by immunofluorescent staining and western blot analysis. Endothelial “permeability” was assessed using a transwell model.

Results

SRL and ERL, at concentrations of 1, 10 and 100 nmol/liter, enhanced oxidative stress (SRL: 24 ± 12%, 29 ± 9%, 41 ± 13% [p < 0.05, in all three cases]; ERL: 13 ± 10%, 27 ± 2%, 40 ± 12% [p < 0.05, in the latter two cases], respectively) on HUVECs, which was inhibited by the anti-oxidant, N-acetyl-cysteine (NAC) and, to a lesser extent, by the specific inhibitor of nitric oxide synthase, N-Ω-nitro-l-arginine methylester. By the use of NAC, VE-cadherin expression remained comparable with control, according to both immunocytochemistry and western blot analysis. Permeability was significantly increased by SRL and ERL at 100 nmol/liter (29.5 ± 6.4% and 33.8 ± 4.2%, respectively); however, co-treatment with NAC abrogated the increased permeability.

Conclusions

EC homeostasis, as indicated by VE-cadherin expression, may be damaged by SRL and ERL, but resolved by the anti-oxidant NAC.

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 Supported by the Katharina Huber-Steiner Foundation, Bern, Switzerland.

PII: S1053-2498(08)00643-8

doi:10.1016/j.healun.2008.08.013

The Journal of Heart and Lung Transplantation
Volume 27, Issue 12 , Pages 1311-1318, December 2008