The direct effect of injectable cyclosporine and its vehicle, cremophor, on endothelial vascular cell adhesion molecule-1 expression. Ricinoleic acid inhibits coronary artery endothelial activation.
As in humans, rabbit coronary artery endothelium basally expresses vascular cell adhesion molecule-1 (VCAM-1). Treatment with parenteral cyclosporine (CsA) to prevent graft rejection in rabbits receiving heterotopic heart transplantation reduced VCAM-1 expression in coronary arteries not only in transplanted, but also in native rabbit hearts. To explore the mechanism of this effect, we co-incubated cultured human saphenous vein endothelial cells for 24 hr with CsA or its vehicle (containing polyoxyethylated castor oil, or Cremophor, and ethanol), at concentrations compatible with those achievable in plasma during administration of parenteral preparations of CsA. Cells were then stimulated with TNF alpha or IL-4 to induce VCAM-1 expression, assessed by a cell-surface enzyme immunoassay. Both CsA and vehicle inhibited IL-4-stimulated VCAM-1 expression in a dose-dependent manner (from [OD mU, mean +/- SEM] 230 +/- 5 to 165 +/- 3 for CsA 50 ng/ml, and to 181 +/- 6 for the corresponding vehicle concentration; P < 0.05 for both comparisons). To investigate whether this vehicle effect also occurs in vivo, we treated 9 New Zealand White rabbits with saline (n = 3), CsA (10 mg/kg/day, n = 3), or vehicle at corresponding doses (n = 3) for 6 weeks. Profiles of coronary arteries (> or = 48 for each group) were semiquantitatively scored (0-5) for VCAM-1 in immunostained heart cross-sections. Administration of both CsA and vehicle significantly reduced VCAM-1 expression compared with saline. Two vehicle components, ethanol and ricinoleic acid, were further evaluated directly on endothelial cells in vitro. While ethanol was ineffective, the monounsaturated fatty acid ricinoleic acid inhibited IL-4-stimulated VCAM-1 expression in a dose-dependent manner (IC50 between 10 and 100 microM). Thus, a fatty acid component of CsA vehicle exerts direct endothelial effects, potentially limiting arterial leukocyte recruitment during parenteral CsA treatment. This observation reveals a novel mechanism for CsA as an inhibitor of leukocyte-endothelial interactions, and furnishes a new potential rationale for the therapeutic action of unsaturated fatty acids in graft coronary disease.
De Caterina
R
R
Vascular Medicine and Atherosclerosis Unit, Cardiovascular Division, Brigham and Women's Hospital-Harvard Medical School, Boston, Massachusetts 02115, USA.
Tanaka
H
H
Nakagawa
T
T
Hauptman
P J
PJ
Libby
P
P
D000818:Animals; D015815:Cell Adhesion Molecules / Q000096:biosynthesis*; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology*; D016207:Cytokines / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism*; D006321:Heart / Q000187:drug effects; D016027:Heart Transplantation; D006801:Humans; D066298:In Vitro Techniques; D009206:Myocardium / Q000378:metabolism; D014677:Pharmaceutical Vehicles / Q000494:pharmacology; D011092:Polyethylene Glycols / Q000494:pharmacology*; D011817:Rabbits; D012277:Ricinoleic Acids / Q000494:pharmacology*; D013268:Stimulation, Chemical; D019010:Vascular Cell Adhesion Molecule-1
D015815:Cell Adhesion Molecules; D016207:Cytokines; D014677:Pharmaceutical Vehicles; D012277:Ricinoleic Acids; D019010:Vascular Cell Adhesion Molecule-1; C022131:cremophor; D011092:Polyethylene Glycols; D016572:Cyclosporine; C030521:ricinoleic acid