Systemic tumor necrosis factor-related apoptosis-inducing ligand delivery shows antiatherosclerotic activity in apolipoprotein E-null diabetic mice.
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.
Secchiero
Paola
P
Department of Morphology and Embryology, University of Ferrara, Ferrara, Italy.
Candido
Riccardo
R
Corallini
Federica
F
Zacchigna
Serena
S
Toffoli
Barbara
B
Rimondi
Erika
E
Fabris
Bruno
B
Giacca
Mauro
M
Zauli
Giorgio
G
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
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