{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T08:10:52Z","timestamp":1770279052243,"version":"3.49.0"},"reference-count":36,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"10","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["ATVB"],"published-print":{"date-parts":[[2013,10]]},"abstract":"<jats:sec>\n            <jats:title>Objective\u2014<\/jats:title>\n            <jats:p>Sirolimus (SRL) is an immunosuppressant drug used to prevent rejection in organ transplantation and neointimal hyperplasia when delivered from drug-eluting stents. Major side effects of SRL include edema and local collection of intimal lipid deposits at drug-eluting stent sites, 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.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Approach and Results\u2014<\/jats:title>\n            <jats:p>Cultured human aortic endothelial cells (HAECs) 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, on EBF. EBF, measured by transendothelial electrical resistance, was impaired in HAECs when treated with SRL or small interfering RNA for FKBP12.6 and reversed when pretreated with ryanodine, a stabilizer of ryanodine receptor 2 intracellular calcium release channels. Intracellular calcium increased in HAECs treated with SRL and normalized with ryanodine pretreatment. SRL-treated HAECs demonstrated increases in protein kinase C-\u03b1 phosphorylation, a calcium sensitive serine\/threonine kinase important in vascular endothelial (VE) cadherin barrier function through its interaction with p120-catenin (p120). Immunostaining of HAECs, human coronary and mouse aortic endothelium treated with SRL showed disruption of p120\u2013VE cadherin interaction treated with SRL. SRL impairment of HAEC EBF was reduced with protein kinase C-\u03b1 small interfering RNA. Mice treated with SRL demonstrated increased vascular permeability by Evans blue albumin extravasation in the lungs, heart, and aorta.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions\u2014<\/jats:title>\n            <jats:p>SRL-FKBP12.6 impairs EBF by activation of protein kinase C-\u03b1 and downstream disruption of the p120\u2013VE cadherin interaction in vascular endothelium. These data suggest this mechanism may be an important contributor of SRL side effects related to impaired EBF.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/atvbaha.113.301659","type":"journal-article","created":{"date-parts":[[2013,7,26]],"date-time":"2013-07-26T11:55:53Z","timestamp":1374839753000},"page":"2425-2431","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":59,"title":["Sirolimus-FKBP12.6 Impairs Endothelial Barrier Function Through Protein Kinase C-\u03b1 Activation and Disruption of the p120\u2013Vascular Endothelial Cadherin Interaction"],"prefix":"10.1161","volume":"33","author":[{"given":"Anwer","family":"Habib","sequence":"first","affiliation":[{"name":"From the Department of Medicine, Emory University School of Medicine, Atlanta, GA (A.H., V.K., R.P., H.A., K.P., A.V.F.); and CV Path Institute, Inc, Gaithersburg, MD (Q.C., F.D.K.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vinit","family":"Karmali","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Emory University School of Medicine, Atlanta, GA (A.H., V.K., R.P., H.A., K.P., A.V.F.); and CV Path Institute, Inc, Gaithersburg, MD (Q.C., F.D.K.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rohini","family":"Polavarapu","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Emory University School of Medicine, Atlanta, GA (A.H., V.K., R.P., H.A., K.P., A.V.F.); and CV Path Institute, Inc, Gaithersburg, MD (Q.C., F.D.K.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hirokuni","family":"Akahori","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Emory University School of Medicine, Atlanta, GA (A.H., V.K., R.P., H.A., K.P., A.V.F.); and CV Path Institute, Inc, Gaithersburg, MD (Q.C., F.D.K.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qi","family":"Cheng","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Emory University School of Medicine, Atlanta, GA (A.H., V.K., R.P., H.A., K.P., A.V.F.); and CV Path Institute, Inc, Gaithersburg, MD (Q.C., F.D.K.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kim","family":"Pachura","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Emory University School of Medicine, Atlanta, GA (A.H., V.K., R.P., H.A., K.P., A.V.F.); and CV Path Institute, Inc, Gaithersburg, MD (Q.C., F.D.K.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frank D.","family":"Kolodgie","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Emory University School of Medicine, Atlanta, GA (A.H., V.K., R.P., H.A., K.P., A.V.F.); and CV Path Institute, Inc, Gaithersburg, MD (Q.C., F.D.K.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aloke V.","family":"Finn","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Emory University School of Medicine, Atlanta, GA (A.H., V.K., R.P., H.A., K.P., A.V.F.); and CV Path Institute, Inc, Gaithersburg, MD (Q.C., 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