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

Oroszlán, Melinda; Bieri, Martin; Ligeti, Nathalie; Farkas, Anikó; Koestner, Simon C.; Meier, Bernhard; Mohaçsi, Paul

doi:10.1016/j.healun.2008.08.013

Cited by 8 publications

(4 citation statements)

References 33 publications

(29 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previous studies examining EBF and SRL have centered on the mTOR signaling pathway in with equivocal results 6, 7, 25, 26 . Downstream effectors of the mTOR signaling pathway such as Akt/PKB, a serine/threonine kinase and downstream effector of mTOR complex 2 (mTORC2), have been proposed to regulate endothelial permeability however results differ 6, 7, 25-27 .…”

Section: Discussionmentioning

confidence: 99%

“…Downstream effectors of the mTOR signaling pathway such as Akt/PKB, a serine/threonine kinase and downstream effector of mTOR complex 2 (mTORC2), have been proposed to regulate endothelial permeability however results differ 6, 7, 25-27 . VE cadherin content however are consistently decreased by SRL treatment suggesting the SRL may affect VE cadherin content and vascular endothelial homeostasis regardless of the model used 6, 7, 25 . Studies suggest that p120-catenin interaction with VE cadherin may act as a set point for endothelial homeostasis and cellular VE cadherin content 28 .…”

Section: Discussionmentioning

confidence: 99%

“…These side effects limit the therapeutic use of sirolimus and suggest that the drug, when given both systemically and locally, impairs endothelial barrier function (EBF). While the major therapeutic mechanism of SRL is through mTOR inhibition, it is not clear whether mTOR inhibition itself leads to increased vascular permeability 6, 7 . Therefore understanding the underlying mechanisms by which SRL impairs EBF may clarify whether these effects are directly related to mTOR inhibition or may represent off-target effects of SRL.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Sirolimus-FKBP12.6 Impairs Endothelial Barrier Function Through Protein Kinase C-α Activation and Disruption of the p120–Vascular Endothelial Cadherin Interaction

Habib

Karmali

Polavarapu

et al. 2013

ATVB

View full text Add to dashboard Cite

Objective Sirolimus (SRL) is an immunosuppressant drug used to prevent rejection in organ transplantation and neointimal hyperplasia when delivered from drug eluting stents (DES). Major side effects of SRL include edema and local collection of intimal lipid deposits at the DES site suggesting that SRL impairs endothelial barrier function (EBF). The aim of this study was to address the role of SRL on impaired EBF and the potential mechanisms involved. Approach and Results Cultured human aortic endothelial cells (HAEC) and intact human and mouse endothelium was examined to determine the effect of SRL, which binds FKBP12.6 to inhibit the mammalian target of rapamycin (mTOR), on EBF. EBF, measured by transendothelial electrical resistance (TEER), was impaired in HAEC when treated with SRL or siRNA for FKBP12.6 and reversed when pretreated with ryanodine, a stabilizer of RyR2 intracellular calcium release channels. Intracellular calcium increased in HAEC treated with SRL and normalized with ryanodine pretreatment. SRL treated HAEC demonstrated increases in PKCα phosphorylation, a calcium sensitive serine/threonine kinase important in VE cadherin barrier function through its interaction with p120-catenin (p120). Immunostaining of HAEC, human coronary and mouse aortic endothelium showed disruption of p120-VE cadherin interaction treated with SRL. SRL impairment of HAEC EBF was reduced with PKCα siRNA. Mice treated with SRL demonstrated increased vascular permeability by Evans blue albumin extravasation (EBAE) in the lungs, heart and aorta. Conclusions SRL-FKBP12.6 impairs EBF by activation of PKCα and downstream disruption of the p120-VE cadherin in vascular endothelium. These data suggest this mechanism may be an important contributor of SRL side effects related to impaired EBF.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Sirolimus-FKBP12.6 Impairs Endothelial Barrier Function Through Protein Kinase C-α Activation and Disruption of the p120–Vascular Endothelial Cadherin Interaction

Habib

Karmali

Polavarapu

et al. 2013

ATVB

View full text Add to dashboard Cite

show abstract

“…Another and not necessarily alternative explanation is that mTOR inhibitors may increase capillary permeability through decreased endothelial-cadherin expression, in particular when the oxidative stress is increased. 33 This would allow enhanced fluid ultrafiltration through the capillary wall with secondary interstitial imbibition and edema, which, in turn, might account for the increasing parenchyma volume detected by CT scan evaluation during sirolimus therapy. Of note, noncystic parenchymal enlargement after discontinuation of the mTOR inhibitor everolimus was recently reported in rat polycystic kidney disease model.…”

Section: Morphologic Outcomesmentioning

confidence: 99%

Sirolimus Therapy to Halt the Progression of ADPKD

Perico

Antiga²,

Caroli

et al. 2010

Journal of the American Society of Nephrology

158

119

View full text Add to dashboard Cite

Activation of mammalian target of rapamycin (mTOR) pathways may contribute to uncontrolled cell proliferation and secondary cyst growth in patients with autosomal dominant polycystic kidney disease (ADPKD). To assess the effects of mTOR inhibition on disease progression, we performed a randomized, crossover study (The SIRENA Study) comparing a 6-month treatment with sirolimus or conventional therapy alone on the growth of kidney volume and its compartments in 21 patients with ADPKD and GFR Ն40 ml/min per 1.73 m 2 . In 10 of the 15 patients who completed the study, aphthous stomatitis complicated sirolimus treatment but was effectively controlled by topical therapy. Compared with pretreatment, posttreatment mean total kidney volume increased less on sirolimus (46 Ϯ 81 ml; P ϭ 0.047) than on conventional therapy (70 Ϯ 72 ml; P ϭ 0.002), but we did not detect a difference between the two treatments (P ϭ 0.45). Cyst volume was stable on sirolimus and increased by 55 Ϯ 75 ml (P ϭ 0.013) on conventional therapy, whereas parenchymal volume increased by 26 Ϯ 30 ml (P ϭ 0.005) on sirolimus and was stable on conventional therapy. Percentage changes in cyst and parenchyma volumes were significantly different between the two treatment periods. Sirolimus had no appreciable effects on intermediate volume and GFR. Albuminuria and proteinuria marginally but significantly increased during sirolimus treatment. In summary, sirolimus halted cyst growth and increased parenchymal volume in patients with ADPKD. Whether these effects translate into improved long-term outcomes requires further investigation.

show abstract

Anti-HLA I antibodies induce VEGF production by endothelial cells, which increases proliferation and paracellular permeability

Bieri¹,

Oroszlán²,

Farkas³

et al. 2009

The International Journal of Biochemistry & Cell Biology

View full text Add to dashboard Cite

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

Cited by 8 publications

References 33 publications

Sirolimus-FKBP12.6 Impairs Endothelial Barrier Function Through Protein Kinase C-α Activation and Disruption of the p120–Vascular Endothelial Cadherin Interaction

Sirolimus-FKBP12.6 Impairs Endothelial Barrier Function Through Protein Kinase C-α Activation and Disruption of the p120–Vascular Endothelial Cadherin Interaction

Sirolimus Therapy to Halt the Progression of ADPKD

Anti-HLA I antibodies induce VEGF production by endothelial cells, which increases proliferation and paracellular permeability

Contact Info

Product

Resources

About