Author + information
- Anwer Habib,
- Vinit Karmali,
- Rohini Polavarapu,
- Hirokuni Akahori,
- Kim Pachura,
- Fumiyuki Otsuka,
- Frank Kolodgie,
- Renu Virmani and
- Aloke Finn
Drug eluting stents (DES) utilizing mTOR inhibitors reduce restenosis but are associated with accelerated neoatherosclerosis. Impaired endothelial barrier function (EBF) is likely contributor to neoatherosclerosis seen in DES.
Human aortic endothelial cells (HAEC) and mouse aortic endothelium (MAE) were examined to determine the effect of sirolimus (SRL), an mTOR inhibitor, on EBF.
EBF, measured by transendothelial electrical resistance, was impaired in HAEC with SRL treatment or transfection with siRNA for FKBP12.6. This impairment was reversed when pretreated with ryanodine, a stabilizer of RyR2 Ca2+ release channels. Intracellular Ca2+ increased in HAEC treated with SRL and normalized with ryanodine. HAEC treated with SRL demonstrated increases in PKCalpha phosphorylation, a serine/threonine kinase important in VE cadherin barrier function through its interaction with p120–catenin. Immunostaining of both HAEC and MAE showed disruption of VE cadherin (green) and p120 (red) in cells/aortas treated with SRL (figure). SRL impairment of EBF was abolished by HAEC transfection with PKCalpha siRNA. Mice treated with SRL demonstrated increased MAE permeability measured by Evans blue.
SRL binding to FKBP12.6 impairs EBF by increasing intracellular Ca2+ concentration leading to PKCalpha activation and disruption of the VE Cadherin–p120 interaction. Poor EBF may contribute to accelerated neoatherosclerosis seen within DES that utilize mTOR inhibitors.
West, Room 2004
Saturday, March 09, 2013, 8:45 a.m.–8:55 a.m.
Session Title: Translational Science
Abstract Category: 52. TCT@ACC–i2: Translation and Pre–clinical Research
Presentation Number: 2902–7
- 2013 American College of Cardiology Foundation