ABSTRACT
To determine whether insulin action on endothelial cells promotes or protects against atherosclerosis, we generated apolipoprotein E null mice in which the insulin receptor gene was intact or conditionally deleted in vascular endothelial cells. Insulin sensitivity, glucose tolerance, plasma lipids, and blood pressure were not different between the two groups, but atherosclerotic lesion size was more than 2-fold higher in mice lacking endothelial insulin signaling. Endothelium-dependent vasodilation was impaired and endothelial cell VCAM-1 expression was increased in these animals. Adhesion of mononuclear cells to endothelium in vivo was increased 4-fold compared with controls but reduced to below control values by a VCAM-1-blocking antibody. These results provide definitive evidence that loss of insulin signaling in endothelium, in the absence of competing systemic risk factors, accelerates atherosclerosis. Therefore, improving insulin sensitivity in the endothelium of patients with insulin resistance or type 2 diabetes may prevent cardiovascular complications.
Subject(s)
Apolipoproteins E/genetics , Atherosclerosis/etiology , Endothelial Cells/metabolism , Endothelium, Vascular/metabolism , Insulin/metabolism , Animals , Apolipoproteins E/deficiency , Apolipoproteins E/metabolism , Cell Adhesion , Endothelium, Vascular/cytology , Mice , Mice, Knockout , Risk Factors , Signal Transduction , Vascular Cell Adhesion Molecule-1/metabolism , VasodilationABSTRACT
Anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) is a T-cell malignancy in which ALK expression is a consequence of the t(2;5) or a variant translocation involving Chromosome 2. For the most part, this disease presents in the pediatric population and most, but not all, patients are successfully treated. Although the t(2;5) product nucleophosmin-ALK has been extensively studied for its transforming properties, very little is known regarding cooperative genetic mutations that may contribute to lymphomagenesis and may predict survival outcome, specifically in a purely pediatric population. We set out to determine the frequency and positions of genomic imbalances in this relatively rare disease. We collected biopsy material from 15 UK-resident children with ALK-expressing ALCL. We performed array comparative genomic hybridization at a resolution of 1 MB using DNA isolated from tumor tissue. Some of the more common genomic gains were confirmed by quantitative PCR. Regions of genomic gain were far more common than losses and were most often detected on chromosomes 1-4, 5-12, 14, and 17, with Chromosome 11 being the most frequent site of genomic imbalances. Patients with 14 or fewer imbalances had a lower overall 3-year survival (87.5-40%, P = 0.14) as did patients with gains in the regions of DDB1 or BIRC5. A range of genomic imbalances exist in ALK-expressing ALCL of a pediatric origin, with a greater number associated with poorer overall survival.
