title: Systemic tumor necrosis factor-related apoptosis-inducing ligand delivery shows antiatherosclerotic activity in apolipoprotein E-null diabetic mice.
abstract: BACKGROUND
  Although in vitro studies have suggested that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) might be involved in vascular biology, its potential role in the pathogenesis and/or treatment of atherosclerosis has not been investigated.
  
  
  RESULTS
  Both recombinant human TRAIL and an adeno-associated virus vector expressing human TRAIL were used to deliver TRAIL in apolipoprotein E (apoE)-null mice in which diabetes mellitus was induced by destruction of islet cells with streptozotocin. Diabetes in apoE-null mice was associated with a significant increase in atherosclerotic plaque area and complexity in the aorta as assessed by a marked increase in interstitial collagen, cellular proliferation, and macrophage infiltration and a focal loss of endothelial coverage. Repeated intraperitoneal injections of recombinant human TRAIL and a single intravenous injection of adeno-associated virus-human TRAIL significantly attenuated the development of atherosclerotic plaques in apoE-null animals. TRAIL also markedly affected the cellular composition of plaque lesions by inducing apoptosis of infiltrating macrophages and increasing the vascular smooth muscle cell content. Moreover, TRAIL promoted the in vitro migration of cultured human aortic vascular smooth muscle cells but not of monocytes or macrophages. Conversely, TRAIL selectively induced apoptosis of human cultured macrophages but not of vascular smooth muscle cells.
  
  
  CONCLUSIONS
  Overall, data from the present study indicate that atherosclerosis in diabetic apoE-null mice is ameliorated by systemic TRAIL administration and that adeno-associated virus-mediated TRAIL gene delivery might represent an innovative method for the therapy of diabetic vascular diseases.
authors.affiliation: Department of Morphology and Embryology, University of Ferrara, Ferrara, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Secchiero
authors.forename: Riccardo
authors.initials: R
authors.lastname: Candido
authors.forename: Federica
authors.initials: F
authors.lastname: Corallini
authors.forename: Serena
authors.initials: S
authors.lastname: Zacchigna
authors.forename: Barbara
authors.initials: B
authors.lastname: Toffoli
authors.forename: Erika
authors.initials: E
authors.lastname: Rimondi
authors.forename: Bruno
authors.initials: B
authors.lastname: Fabris
authors.forename: Mauro
authors.initials: M
authors.lastname: Giacca
authors.forename: Giorgio
authors.initials: G
authors.lastname: Zauli
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000008:administration & dosage* / Q000494:pharmacology; D050197:Atherosclerosis / Q000188:drug therapy* / Q000209:etiology* / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D006801:Humans; D008264:Macrophages / Q000473:pathology; D008562:Membrane Glycoproteins / Q000008:administration & dosage* / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects; D013311:Streptozocin; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage* / Q000494:pharmacology
chemical_list: D001057:Apolipoproteins E; D051017:Apoptosis Regulatory Proteins; D008562:Membrane Glycoproteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C505654:Tnfsf10 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D013311:Streptozocin