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(Circulation. 2006;114:1522-1530.)
© 2006 American Heart Association, Inc.

Vascular Medicine

Systemic Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand Delivery Shows Antiatherosclerotic Activity in Apolipoprotein E–Null Diabetic Mice

Paola Secchiero, PhD; Riccardo Candido, MD, PhD; Federica Corallini, PhD; Serena Zacchigna, MD, PhD; Barbara Toffoli, PhD; Erika Rimondi, PhD; Bruno Fabris, MD; Mauro Giacca, MD, PhD; Giorgio Zauli, MD, PhD

From the Department of Morphology and Embryology, University of Ferrara, Ferrara (P.S., E.R.); Departments of Clinical Medicine and Neurology (R.C., B.T., B.F.) and Normal Human Morphology (F.C., S.Z., E.R., M.G., G.Z.), University of Trieste, Trieste; Diabetic Center, A.S.S. 1 Triestina, Trieste (R.C.); and Medicine Laboratory, International Center for Genetic Engineering and Biotechnology, Trieste (S.Z., M.G.), Italy.

Correspondence to Giorgio Zauli, MD, PhD, Department of Normal Human Morphology, University of Trieste, Via Manzoni 16, 34138 Trieste, Italy. E-mail zauli{at}units.it

Received February 20, 2006; de novo received June 5, 2006; revision received July 28, 2006; accepted July 31, 2006.

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.

Methods and 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.

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