Systemic tumor necrosis factor-related apoptosis-inducing ligand delivery shows antiatherosclerotic activity in apolipoprotein E-null diabetic mice

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

Research output: Contribution to journalArticle

120 Citations (Scopus)

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. 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.

Original languageEnglish
Pages (from-to)1522-1530
Number of pages9
JournalCirculation
Volume114
Issue number14
DOIs
Publication statusPublished - Oct 2006

Fingerprint

Apolipoproteins E
Tumor Necrosis Factor-alpha
Apoptosis
Ligands
Dependovirus
Macrophages
Vascular Smooth Muscle
Smooth Muscle Myocytes
Atherosclerotic Plaques
Atherosclerosis
Diabetic Angiopathies
Investigational Therapies
Streptozocin
Intraperitoneal Injections
Islets of Langerhans
Intravenous Injections
Blood Vessels
Aorta
Monocytes
Diabetes Mellitus

Keywords

  • Atherosclerosis
  • Diabetes mellitus
  • Gene therapy
  • Immunohistochemistry
  • Plaque

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Systemic tumor necrosis factor-related apoptosis-inducing ligand delivery shows antiatherosclerotic activity in apolipoprotein E-null diabetic mice. / Secchiero, Paola; Candido, Riccardo; Corallini, Federica; Zacchigna, Serena; Toffoli, Barbara; Rimondi, Erika; Fabris, Bruno; Giacca, Mauro; Zauli, Giorgio.

In: Circulation, Vol. 114, No. 14, 10.2006, p. 1522-1530.

Research output: Contribution to journalArticle

Secchiero, P, Candido, R, Corallini, F, Zacchigna, S, Toffoli, B, Rimondi, E, Fabris, B, Giacca, M & Zauli, G 2006, 'Systemic tumor necrosis factor-related apoptosis-inducing ligand delivery shows antiatherosclerotic activity in apolipoprotein E-null diabetic mice', Circulation, vol. 114, no. 14, pp. 1522-1530. https://doi.org/10.1161/CIRCULATIONAHA.106.643841
Secchiero, Paola ; Candido, Riccardo ; Corallini, Federica ; Zacchigna, Serena ; Toffoli, Barbara ; Rimondi, Erika ; Fabris, Bruno ; Giacca, Mauro ; Zauli, Giorgio. / Systemic tumor necrosis factor-related apoptosis-inducing ligand delivery shows antiatherosclerotic activity in apolipoprotein E-null diabetic mice. In: Circulation. 2006 ; Vol. 114, No. 14. pp. 1522-1530.
@article{c7654e1feabe4a72ba4e8deec77f0bc2,
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. 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.",
keywords = "Atherosclerosis, Diabetes mellitus, Gene therapy, Immunohistochemistry, Plaque",
author = "Paola Secchiero and Riccardo Candido and Federica Corallini and Serena Zacchigna and Barbara Toffoli and Erika Rimondi and Bruno Fabris and Mauro Giacca and Giorgio Zauli",
year = "2006",
month = "10",
doi = "10.1161/CIRCULATIONAHA.106.643841",
language = "English",
volume = "114",
pages = "1522--1530",
journal = "Circulation",
issn = "0009-7322",
publisher = "Lippincott Williams and Wilkins",
number = "14",

}

TY - JOUR

T1 - Systemic tumor necrosis factor-related apoptosis-inducing ligand delivery shows antiatherosclerotic activity in apolipoprotein E-null diabetic mice

AU - Secchiero, Paola

AU - Candido, Riccardo

AU - Corallini, Federica

AU - Zacchigna, Serena

AU - Toffoli, Barbara

AU - Rimondi, Erika

AU - Fabris, Bruno

AU - Giacca, Mauro

AU - Zauli, Giorgio

PY - 2006/10

Y1 - 2006/10

N2 - 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.

AB - 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.

KW - Atherosclerosis

KW - Diabetes mellitus

KW - Gene therapy

KW - Immunohistochemistry

KW - Plaque

UR - http://www.scopus.com/inward/record.url?scp=33749531597&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33749531597&partnerID=8YFLogxK

U2 - 10.1161/CIRCULATIONAHA.106.643841

DO - 10.1161/CIRCULATIONAHA.106.643841

M3 - Article

VL - 114

SP - 1522

EP - 1530

JO - Circulation

JF - Circulation

SN - 0009-7322

IS - 14

ER -