Retroviral gene therapy in apoE-deficient mice: ApoE expression in the artery wall reduces early foam cell lesion formation

A. H. Hasty, M. F. Linton, S. J. Brandt, V. R. Babaev, L. A. Gleaves, Sergio Fazio

Research output: Contribution to journalArticle

101 Citations (Scopus)

Abstract

Background - Apolipoprotein E (apoE) has long been known to play an important role in the clearance of plasma lipoproteins. More recently, a direct role for apoE in delaying atherogenesis has been proposed. Macrophage production of apoE in the artery wall has been demonstrated to provide protection against atherosclerotic lesion development independently from its role in lipoprotein clearance. However, whether macrophage apoE can affect lesion growth at all stages of atherogenesis remains to be established. Methods and Results - To evaluate the role of macrophage apoE in different stages of atherogenesis, as well as to establish a novel gene therapy approach to atherosclerotic vascular disease, we used an apoE-expressing retrovirus to transduce apoE-deficient (-/-) bone marrow for transplantation into apoE(-/-) recipient mice. Three weeks after bone marrow transplantation, apoE was expressed from arterial macrophages and was detectable in plasma associated with lipoproteins at 0.5% to 1% of normal levels but did not affect plasma cholesterol levels. We used 2 groups of recipient mice: younger mice with lesions consisting primarily of foam cells and older mice with more advanced lesions. When either the mouse or human apoE transgenes were expressed in mice from 5 to 13 weeks of age, there was a significant reduction in lesion area, whereas no effects were detected in mice that expressed apoE from 10 to 26 weeks of age. Conclusions - We demonstrate that arterial macrophage apoE secretion can delay atherogenesis if expressed during foam cell formation but is not beneficial during the later stages of atherogenesis. These data also provide evidence that apoE transgene expression from arterial macrophages may have therapeutic applications.

Original languageEnglish (US)
Pages (from-to)2571-2576
Number of pages6
JournalCirculation
Volume99
Issue number19
StatePublished - May 18 1999
Externally publishedYes

Fingerprint

Foam Cells
Apolipoproteins E
Genetic Therapy
Arteries
Macrophages
Atherosclerosis
Lipoproteins
Bone Marrow Transplantation
Transgenes
Retroviridae
Vascular Diseases

Keywords

  • Apolipoproteins
  • Atherosclerosis
  • Cholesterol
  • Genes

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Hasty, A. H., Linton, M. F., Brandt, S. J., Babaev, V. R., Gleaves, L. A., & Fazio, S. (1999). Retroviral gene therapy in apoE-deficient mice: ApoE expression in the artery wall reduces early foam cell lesion formation. Circulation, 99(19), 2571-2576.

Retroviral gene therapy in apoE-deficient mice : ApoE expression in the artery wall reduces early foam cell lesion formation. / Hasty, A. H.; Linton, M. F.; Brandt, S. J.; Babaev, V. R.; Gleaves, L. A.; Fazio, Sergio.

In: Circulation, Vol. 99, No. 19, 18.05.1999, p. 2571-2576.

Research output: Contribution to journalArticle

Hasty, AH, Linton, MF, Brandt, SJ, Babaev, VR, Gleaves, LA & Fazio, S 1999, 'Retroviral gene therapy in apoE-deficient mice: ApoE expression in the artery wall reduces early foam cell lesion formation', Circulation, vol. 99, no. 19, pp. 2571-2576.
Hasty, A. H. ; Linton, M. F. ; Brandt, S. J. ; Babaev, V. R. ; Gleaves, L. A. ; Fazio, Sergio. / Retroviral gene therapy in apoE-deficient mice : ApoE expression in the artery wall reduces early foam cell lesion formation. In: Circulation. 1999 ; Vol. 99, No. 19. pp. 2571-2576.
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