Published Online
on September 25, 2006

A more recent version of this article appeared on October 3, 2006

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Submitted on February 20, 2006
Revised on July 28, 2006
Accepted on July 31, 2006

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, and 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.

^* To whom correspondence should be addressed. E-mail: zauli{at}units.it.

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.

Key words: atherosclerosis • diabetes mellitus • gene therapy • immunohistochemistry • plaque

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