Adenoviral gene transfer of fortilin attenuates neointima formation through suppression of vascular smooth muscle cell proliferation and migration

David A. Tulis, Zakar H. Mnjoyan, Rachel L. Schiesser, Harnath S. Shelat, Alida J. Evans, Pierre Zoldhelyi, Kenichi Fujise

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Background - Fortilin, a recently characterized nuclear antiapoptotic factor structurally distinct from inhibitor of apoptosis proteins (IAPs) and Bcl-2 family member proteins, has been suggested to be involved in cell survival and regulation of apoptosis within the cardiovascular system. In this continued investigation, we characterized the influence of adenovirus-mediated fortilin (Ad-fortilin) gene delivery on vascular remodeling after experimental angioplasty. Methods and Results - Vessel wall expression of Ad-fortilin or adenoviral luciferase (Ad-luc) was demonstrated 72 hours and 14 days after rat carotid artery (CA) balloon angioplasty. Morphometric analyses 14 days after injury revealed significantly diminished neointima development in the Ad-fortilin-treated CAs compared with Ad-luc or PBS controls, with no changes in medial wall morphometry observed between the 3 groups. The Ad-fortilin-treated CAs demonstrated a 50% reduction in medial wall proliferating cell nuclear antigen (PCNA) labeling after 72 hours, with significantly reduced neointimal and medial wall PCNA labeling and cell counts after 14 days. Terminal dUTP nick-end labeling results and morphological changes characteristic of programmed cell death suggest a trend toward reduced apoptosis in the fortilin-transfected balloon-injured vessels compared with Ad-luc injured controls. Temporal analysis of human aorta smooth muscle cell (SMC) proliferation demonstrated a marked time-dependent inhibition in Ad-fortilin treated SMCs without the influence of elevated apoptosis. Thymidine incorporation was significantly inhibited in the Ad-fortilin-treated cells compared with Ad-luc controls. Ad-fortilin transfected SMCs also demonstrated significantly decreased migration compared with Ad-luc controls. Conclusions - These cumulative results suggest that the novel antiapoptotic protein fortilin may play important redundant pathophysiological roles in modulating the vascular response to experimental angioplasty through suppression of SMC proliferation and migration concomitant with reduction of vessel wall apoptosis.

Original languageEnglish (US)
Pages (from-to)98-105
Number of pages8
JournalCirculation
Volume107
Issue number1
DOIs
StatePublished - Jan 7 2003
Externally publishedYes

Fingerprint

Neointima
Vascular Smooth Muscle
Adenoviridae
Smooth Muscle Myocytes
Cell Movement
Cell Proliferation
Luciferases
Genes
Apoptosis
Proliferating Cell Nuclear Antigen
Angioplasty
Inhibitor of Apoptosis Proteins
Balloon Angioplasty
Cardiovascular System
Transfer (Psychology)
Carotid Arteries
Thymidine
Blood Vessels
Aorta
Cell Survival

Keywords

  • Angioplasty
  • Carotid arteries
  • Gene therapy
  • Proteins
  • Remodeling

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Adenoviral gene transfer of fortilin attenuates neointima formation through suppression of vascular smooth muscle cell proliferation and migration. / Tulis, David A.; Mnjoyan, Zakar H.; Schiesser, Rachel L.; Shelat, Harnath S.; Evans, Alida J.; Zoldhelyi, Pierre; Fujise, Kenichi.

In: Circulation, Vol. 107, No. 1, 07.01.2003, p. 98-105.

Research output: Contribution to journalArticle

Tulis, David A. ; Mnjoyan, Zakar H. ; Schiesser, Rachel L. ; Shelat, Harnath S. ; Evans, Alida J. ; Zoldhelyi, Pierre ; Fujise, Kenichi. / Adenoviral gene transfer of fortilin attenuates neointima formation through suppression of vascular smooth muscle cell proliferation and migration. In: Circulation. 2003 ; Vol. 107, No. 1. pp. 98-105.
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T1 - Adenoviral gene transfer of fortilin attenuates neointima formation through suppression of vascular smooth muscle cell proliferation and migration

AU - Tulis, David A.

AU - Mnjoyan, Zakar H.

AU - Schiesser, Rachel L.

AU - Shelat, Harnath S.

AU - Evans, Alida J.

AU - Zoldhelyi, Pierre

AU - Fujise, Kenichi

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N2 - Background - Fortilin, a recently characterized nuclear antiapoptotic factor structurally distinct from inhibitor of apoptosis proteins (IAPs) and Bcl-2 family member proteins, has been suggested to be involved in cell survival and regulation of apoptosis within the cardiovascular system. In this continued investigation, we characterized the influence of adenovirus-mediated fortilin (Ad-fortilin) gene delivery on vascular remodeling after experimental angioplasty. Methods and Results - Vessel wall expression of Ad-fortilin or adenoviral luciferase (Ad-luc) was demonstrated 72 hours and 14 days after rat carotid artery (CA) balloon angioplasty. Morphometric analyses 14 days after injury revealed significantly diminished neointima development in the Ad-fortilin-treated CAs compared with Ad-luc or PBS controls, with no changes in medial wall morphometry observed between the 3 groups. The Ad-fortilin-treated CAs demonstrated a 50% reduction in medial wall proliferating cell nuclear antigen (PCNA) labeling after 72 hours, with significantly reduced neointimal and medial wall PCNA labeling and cell counts after 14 days. Terminal dUTP nick-end labeling results and morphological changes characteristic of programmed cell death suggest a trend toward reduced apoptosis in the fortilin-transfected balloon-injured vessels compared with Ad-luc injured controls. Temporal analysis of human aorta smooth muscle cell (SMC) proliferation demonstrated a marked time-dependent inhibition in Ad-fortilin treated SMCs without the influence of elevated apoptosis. Thymidine incorporation was significantly inhibited in the Ad-fortilin-treated cells compared with Ad-luc controls. Ad-fortilin transfected SMCs also demonstrated significantly decreased migration compared with Ad-luc controls. Conclusions - These cumulative results suggest that the novel antiapoptotic protein fortilin may play important redundant pathophysiological roles in modulating the vascular response to experimental angioplasty through suppression of SMC proliferation and migration concomitant with reduction of vessel wall apoptosis.

AB - Background - Fortilin, a recently characterized nuclear antiapoptotic factor structurally distinct from inhibitor of apoptosis proteins (IAPs) and Bcl-2 family member proteins, has been suggested to be involved in cell survival and regulation of apoptosis within the cardiovascular system. In this continued investigation, we characterized the influence of adenovirus-mediated fortilin (Ad-fortilin) gene delivery on vascular remodeling after experimental angioplasty. Methods and Results - Vessel wall expression of Ad-fortilin or adenoviral luciferase (Ad-luc) was demonstrated 72 hours and 14 days after rat carotid artery (CA) balloon angioplasty. Morphometric analyses 14 days after injury revealed significantly diminished neointima development in the Ad-fortilin-treated CAs compared with Ad-luc or PBS controls, with no changes in medial wall morphometry observed between the 3 groups. The Ad-fortilin-treated CAs demonstrated a 50% reduction in medial wall proliferating cell nuclear antigen (PCNA) labeling after 72 hours, with significantly reduced neointimal and medial wall PCNA labeling and cell counts after 14 days. Terminal dUTP nick-end labeling results and morphological changes characteristic of programmed cell death suggest a trend toward reduced apoptosis in the fortilin-transfected balloon-injured vessels compared with Ad-luc injured controls. Temporal analysis of human aorta smooth muscle cell (SMC) proliferation demonstrated a marked time-dependent inhibition in Ad-fortilin treated SMCs without the influence of elevated apoptosis. Thymidine incorporation was significantly inhibited in the Ad-fortilin-treated cells compared with Ad-luc controls. Ad-fortilin transfected SMCs also demonstrated significantly decreased migration compared with Ad-luc controls. Conclusions - These cumulative results suggest that the novel antiapoptotic protein fortilin may play important redundant pathophysiological roles in modulating the vascular response to experimental angioplasty through suppression of SMC proliferation and migration concomitant with reduction of vessel wall apoptosis.

KW - Angioplasty

KW - Carotid arteries

KW - Gene therapy

KW - Proteins

KW - Remodeling

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