BACKGROUND: Mitochondria-mediated apoptotic signaling contributes to microvascular hyperpermeability. We hypothesized that cyclosporine A (CsA), which protects mitochondrial transition pores, would attenuate hyperpermeability independent of its calcineurin inhibitory property. METHODS: Hyperpermeability was induced in microvascular endothelial cell monolayers using proapoptotic BAK or active caspase-3 after CsA or a specific calcineurin inhibitor, calcineurin autoinhibitory peptide (CIP), treatment. Permeability was measured based on fluorescein isothiocyanate-albumin flux across the monolayers. Mitochondrial transmembrane potential (MTP) was determined using 5,5',6,6'-tetrachoro-1,1',3,3'-tetraethylbenzimidazolyl carbocyanine iodide. Mitochondrial release of cytochrome c was measured using an enzyme-linked immunosorbent assay and caspase-3 activity fluorometrically. RESULTS: CsA-attenuated (10 nmol/L) but not CIP-attenuated (100 mumol/L) BAK induced hyperpermeability (P < .05), CsA- but not CIP-attenuated BAK induced a decrease in MTP and an increase in cytochrome c levels and caspase-3 activity (P < .05). CsA and CIP were ineffective against caspase-3-induced hyperpermeability. CONCLUSIONS: CsA attenuated hyperpermeability by protecting MTP, thus preventing mitochondria-mediated apoptotic signaling. The protective effect of CsA is independent of calcineurin inhibition. Copyright 2010 Elsevier Inc. All rights reserved.
BACKGROUND: Mitochondria-mediated apoptotic signaling contributes to microvascular hyperpermeability. We hypothesized that cyclosporine A (CsA), which protects mitochondrial transition pores, would attenuate hyperpermeability independent of its calcineurin inhibitory property. METHODS: Hyperpermeability was induced in microvascular endothelial cell monolayers using proapoptotic BAK or active caspase-3 after CsA or a specific calcineurin inhibitor, calcineurin autoinhibitory peptide (CIP), treatment. Permeability was measured based on fluorescein isothiocyanate-albumin flux across the monolayers. Mitochondrial transmembrane potential (MTP) was determined using 5,5',6,6'-tetrachoro-1,1',3,3'-tetraethylbenzimidazolyl carbocyanine iodide. Mitochondrial release of cytochrome c was measured using an enzyme-linked immunosorbent assay and caspase-3 activity fluorometrically. RESULTS:CsA-attenuated (10 nmol/L) but not CIP-attenuated (100 mumol/L) BAK induced hyperpermeability (P < .05), CsA- but not CIP-attenuatedBAK induced a decrease in MTP and an increase in cytochrome c levels and caspase-3 activity (P < .05). CsA and CIP were ineffective against caspase-3-induced hyperpermeability. CONCLUSIONS:CsA attenuated hyperpermeability by protecting MTP, thus preventing mitochondria-mediated apoptotic signaling. The protective effect of CsA is independent of calcineurin inhibition. Copyright 2010 Elsevier Inc. All rights reserved.
Authors: F Squadrito; D Altavilla; G Squadrito; M Ferlito; B Deodato; M Arlotta; L Minutoli; G M Campo; A Bova; C Quartarone; G Urna; A Sardella; A Saitta; A P Caputi Journal: Br J Pharmacol Date: 2000-05 Impact factor: 8.739
Authors: Steven M Woolley; Alexander S Farivar; Babu V Naidu; Matthew Rosengart; Robert Thomas; Charles Fraga; Michael S Mulligan Journal: J Thorac Cardiovasc Surg Date: 2004-02 Impact factor: 5.209
Authors: K Murata; Y Motomura; T Tanaka; S Kanno; T Yano; M Onimaru; A Shimoyama; H Nishio; Y Sakai; M Oh-Hora; H Hara; K Fukase; H Takada; S Masuda; S Ohga; S Yamasaki; T Hara Journal: Clin Exp Immunol Date: 2017-07-21 Impact factor: 4.330