title: Gliotoxin inhibits neointimal hyperplasia after vascular injury in rats.
abstract: Neointima formation participates in the pathophysiology of atherosclerosis and restenosis. Proliferation and migration of vascular smooth muscle cells (VSMC) are initial responses to vascular injury. The aim of the present study was to assess the effect of gliotoxin, an inhibitor of nuclear factor (NF)-kappaB, on migration and proliferation of cultured rat VSMC and neointimal formation in injured rat vessels. In cultured VSMC, gliotoxin inhibited the nuclear translocation of the p65 subunit of NF-kappaB in response to inflammatory stimuli. In addition, gliotoxin inhibited VSMC migration and proliferation in response to platelet-derived growth factor-BB. This was associated with a rapid rearrangement of the F-actin and vimentin cytoskeleton. Furthermore, gliotoxin inhibited endothelial cell nuclear translocation of p65, cell surface expression of adhesion molecules such as VCAM-1, ICAM-1 and E-selectin, and monocytic cell adhesion to a cytokine-activated endothelial monolayer. In the rat carotid artery balloon catheter injury model, the systemic administration of gliotoxin for 10 days decreased neointimal hyperplasia and luminal stenosis by up to 90% and decreased the expression of proliferating cell nuclear antigen in the vessel wall by up to 70%, depending on the dose. These observations suggest that gliotoxin favorably regulates the response to vascular injury through actions on VSMC. However, further studies evaluating the therapeutic benefit of gliotoxin in restenosis after balloon angioplasty are required.
authors.affiliation: Fundación Jiménez Díaz y Universidad Autónoma de Madrid, Madrid, España.
authors.forename: Mayte
authors.initials: M
authors.lastname: Pozo
authors.forename: María Concepción
authors.initials: MC
authors.lastname: Izquierdo
authors.forename: Rosario
authors.initials: R
authors.lastname: de Nicolás
authors.forename: Jesús
authors.initials: J
authors.lastname: Egido
authors.forename: Alberto
authors.initials: A
authors.lastname: Ortiz
authors.forename: Jesús
authors.initials: J
authors.lastname: González-Cabrero
mesh_terms: D000199:Actins / Q000378:metabolism; D021581:Active Transport, Cell Nucleus; D000800:Angioplasty, Balloon / Q000009:adverse effects; D000818:Animals; D000077214:Becaplermin; D002317:Cardiovascular Agents / Q000494:pharmacology*; D020212:Carotid Artery Injuries / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D005912:Gliotoxin / Q000494:pharmacology*; D006965:Hyperplasia; D008297:Male; D009000:Monocytes / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012008:Recurrence; D013997:Time Factors; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors / Q000378:metabolism; D014746:Vimentin / Q000378:metabolism
chemical_list: D000199:Actins; D002317:Cardiovascular Agents; D015815:Cell Adhesion Molecules; D010982:Platelet-Derived Growth Factor; D018809:Proliferating Cell Nuclear Antigen; D020574:Proto-Oncogene Proteins c-sis; C498145:Rela protein, rat; D051996:Transcription Factor RelA; D014746:Vimentin; D000077214:Becaplermin; D005912:Gliotoxin