Local adenovirus-mediated transfer of human endothelial nitric oxide synthase reduces luminal narrowing after coronary angioplasty in pigs

Olivier Varenne, Sorin Pislaru, Hilde Gillijns, Natascha Van Pelt, Robert D. Gerard, Pierre Zoldhelyi, Frans Van De Werf, Désiré Collen, Stefan P. Janssens

Research output: Contribution to journalArticle

164 Citations (Scopus)

Abstract

Background - Nitric oxide, synthesized from L-arginine by nitric oxide synthase (NOS), is a vasodilator and inhibits vascular smooth muscle cell (SMC) proliferation and migration. The effects of local NOS gene transfer on restenosis after experimental balloon angioplasty were investigated. Methods and Results - Left anterior descending coronary artery angioplasty was performed in 25 pigs. Animals received an intramural injection of adenovirus (1.5x109 pfu) carrying either the NOS cDNA (AdCMVceNOS) or no cDNA (AdRR5) via the Infiltrator. Local gene transfer efficiency and bioactivity of recombinant protein were assessed after 4 days. Indices of restenosis were evaluated by computerized planimetry on coronary artery sections prepared 28 days after angioplasty. Adenoviral vectors permitted efficient gene delivery to medial SMCs and adventitial cells of coronary arteries. Vascular cGMP levels were depressed after angioplasty from 1.30±0.42 to 0.33±0.20 pmol/mg protein (P<0.05) but were restored after constitutive endothelial (ce) NOS gene transfer to 1.82±0.98 pmol/mg (P<0.05 versus injured group and P=NS versus control). The ratio of the neointimal area to the internal elastic lamina fracture length, maximal neointimal thickness, and percent stenosis were all reduced in AdCMVceNOS- versus AdRR5-transduced pigs (0.59±0.14 versus 0.80±0.19 mm, P=0.02; 0.75±0.21 versus 1.04±0.25 mm, P=0.019; and 53±15% versus 75±11%, P=0.006, respectively). Lumen area was significantly larger (0.70±0.35 mm2 in AdCMVceNOS versus 0.32±0.18 mm2 in AdRR5, P=0.007). Conclusions - Percutaneous adenovirus-mediated NOS gene transfer resulted in efficient local overexpression of functional NOS after angioplasty in coronary arteries. Restored NO production in injured coronary arteries significantly reduced luminal narrowing, most likely through a combined effect on neointima formation and on vessel remodeling after angioplasty.

Original languageEnglish (US)
Pages (from-to)919-926
Number of pages8
JournalCirculation
Volume98
Issue number9
StatePublished - Sep 1 1998

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Nitric Oxide Synthase Type III
Angioplasty
Adenoviridae
Nitric Oxide Synthase
Coronary Vessels
Swine
Genes
Complementary DNA
Neointima
Adventitia
Balloon Angioplasty
Vasodilator Agents
Vascular Smooth Muscle
Recombinant Proteins
Smooth Muscle Myocytes
Cell Movement
Blood Vessels
Arginine
Nitric Oxide
Pathologic Constriction

Keywords

  • Genes
  • Nitric oxide
  • Remodeling
  • Restenosis
  • Vessels

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Varenne, O., Pislaru, S., Gillijns, H., Van Pelt, N., Gerard, R. D., Zoldhelyi, P., ... Janssens, S. P. (1998). Local adenovirus-mediated transfer of human endothelial nitric oxide synthase reduces luminal narrowing after coronary angioplasty in pigs. Circulation, 98(9), 919-926.

Local adenovirus-mediated transfer of human endothelial nitric oxide synthase reduces luminal narrowing after coronary angioplasty in pigs. / Varenne, Olivier; Pislaru, Sorin; Gillijns, Hilde; Van Pelt, Natascha; Gerard, Robert D.; Zoldhelyi, Pierre; Van De Werf, Frans; Collen, Désiré; Janssens, Stefan P.

In: Circulation, Vol. 98, No. 9, 01.09.1998, p. 919-926.

Research output: Contribution to journalArticle

Varenne, O, Pislaru, S, Gillijns, H, Van Pelt, N, Gerard, RD, Zoldhelyi, P, Van De Werf, F, Collen, D & Janssens, SP 1998, 'Local adenovirus-mediated transfer of human endothelial nitric oxide synthase reduces luminal narrowing after coronary angioplasty in pigs', Circulation, vol. 98, no. 9, pp. 919-926.
Varenne O, Pislaru S, Gillijns H, Van Pelt N, Gerard RD, Zoldhelyi P et al. Local adenovirus-mediated transfer of human endothelial nitric oxide synthase reduces luminal narrowing after coronary angioplasty in pigs. Circulation. 1998 Sep 1;98(9):919-926.
Varenne, Olivier ; Pislaru, Sorin ; Gillijns, Hilde ; Van Pelt, Natascha ; Gerard, Robert D. ; Zoldhelyi, Pierre ; Van De Werf, Frans ; Collen, Désiré ; Janssens, Stefan P. / Local adenovirus-mediated transfer of human endothelial nitric oxide synthase reduces luminal narrowing after coronary angioplasty in pigs. In: Circulation. 1998 ; Vol. 98, No. 9. pp. 919-926.
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abstract = "Background - Nitric oxide, synthesized from L-arginine by nitric oxide synthase (NOS), is a vasodilator and inhibits vascular smooth muscle cell (SMC) proliferation and migration. The effects of local NOS gene transfer on restenosis after experimental balloon angioplasty were investigated. Methods and Results - Left anterior descending coronary artery angioplasty was performed in 25 pigs. Animals received an intramural injection of adenovirus (1.5x109 pfu) carrying either the NOS cDNA (AdCMVceNOS) or no cDNA (AdRR5) via the Infiltrator. Local gene transfer efficiency and bioactivity of recombinant protein were assessed after 4 days. Indices of restenosis were evaluated by computerized planimetry on coronary artery sections prepared 28 days after angioplasty. Adenoviral vectors permitted efficient gene delivery to medial SMCs and adventitial cells of coronary arteries. Vascular cGMP levels were depressed after angioplasty from 1.30±0.42 to 0.33±0.20 pmol/mg protein (P<0.05) but were restored after constitutive endothelial (ce) NOS gene transfer to 1.82±0.98 pmol/mg (P<0.05 versus injured group and P=NS versus control). The ratio of the neointimal area to the internal elastic lamina fracture length, maximal neointimal thickness, and percent stenosis were all reduced in AdCMVceNOS- versus AdRR5-transduced pigs (0.59±0.14 versus 0.80±0.19 mm, P=0.02; 0.75±0.21 versus 1.04±0.25 mm, P=0.019; and 53±15{\%} versus 75±11{\%}, P=0.006, respectively). Lumen area was significantly larger (0.70±0.35 mm2 in AdCMVceNOS versus 0.32±0.18 mm2 in AdRR5, P=0.007). Conclusions - Percutaneous adenovirus-mediated NOS gene transfer resulted in efficient local overexpression of functional NOS after angioplasty in coronary arteries. Restored NO production in injured coronary arteries significantly reduced luminal narrowing, most likely through a combined effect on neointima formation and on vessel remodeling after angioplasty.",
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T1 - Local adenovirus-mediated transfer of human endothelial nitric oxide synthase reduces luminal narrowing after coronary angioplasty in pigs

AU - Varenne, Olivier

AU - Pislaru, Sorin

AU - Gillijns, Hilde

AU - Van Pelt, Natascha

AU - Gerard, Robert D.

AU - Zoldhelyi, Pierre

AU - Van De Werf, Frans

AU - Collen, Désiré

AU - Janssens, Stefan P.

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N2 - Background - Nitric oxide, synthesized from L-arginine by nitric oxide synthase (NOS), is a vasodilator and inhibits vascular smooth muscle cell (SMC) proliferation and migration. The effects of local NOS gene transfer on restenosis after experimental balloon angioplasty were investigated. Methods and Results - Left anterior descending coronary artery angioplasty was performed in 25 pigs. Animals received an intramural injection of adenovirus (1.5x109 pfu) carrying either the NOS cDNA (AdCMVceNOS) or no cDNA (AdRR5) via the Infiltrator. Local gene transfer efficiency and bioactivity of recombinant protein were assessed after 4 days. Indices of restenosis were evaluated by computerized planimetry on coronary artery sections prepared 28 days after angioplasty. Adenoviral vectors permitted efficient gene delivery to medial SMCs and adventitial cells of coronary arteries. Vascular cGMP levels were depressed after angioplasty from 1.30±0.42 to 0.33±0.20 pmol/mg protein (P<0.05) but were restored after constitutive endothelial (ce) NOS gene transfer to 1.82±0.98 pmol/mg (P<0.05 versus injured group and P=NS versus control). The ratio of the neointimal area to the internal elastic lamina fracture length, maximal neointimal thickness, and percent stenosis were all reduced in AdCMVceNOS- versus AdRR5-transduced pigs (0.59±0.14 versus 0.80±0.19 mm, P=0.02; 0.75±0.21 versus 1.04±0.25 mm, P=0.019; and 53±15% versus 75±11%, P=0.006, respectively). Lumen area was significantly larger (0.70±0.35 mm2 in AdCMVceNOS versus 0.32±0.18 mm2 in AdRR5, P=0.007). Conclusions - Percutaneous adenovirus-mediated NOS gene transfer resulted in efficient local overexpression of functional NOS after angioplasty in coronary arteries. Restored NO production in injured coronary arteries significantly reduced luminal narrowing, most likely through a combined effect on neointima formation and on vessel remodeling after angioplasty.

AB - Background - Nitric oxide, synthesized from L-arginine by nitric oxide synthase (NOS), is a vasodilator and inhibits vascular smooth muscle cell (SMC) proliferation and migration. The effects of local NOS gene transfer on restenosis after experimental balloon angioplasty were investigated. Methods and Results - Left anterior descending coronary artery angioplasty was performed in 25 pigs. Animals received an intramural injection of adenovirus (1.5x109 pfu) carrying either the NOS cDNA (AdCMVceNOS) or no cDNA (AdRR5) via the Infiltrator. Local gene transfer efficiency and bioactivity of recombinant protein were assessed after 4 days. Indices of restenosis were evaluated by computerized planimetry on coronary artery sections prepared 28 days after angioplasty. Adenoviral vectors permitted efficient gene delivery to medial SMCs and adventitial cells of coronary arteries. Vascular cGMP levels were depressed after angioplasty from 1.30±0.42 to 0.33±0.20 pmol/mg protein (P<0.05) but were restored after constitutive endothelial (ce) NOS gene transfer to 1.82±0.98 pmol/mg (P<0.05 versus injured group and P=NS versus control). The ratio of the neointimal area to the internal elastic lamina fracture length, maximal neointimal thickness, and percent stenosis were all reduced in AdCMVceNOS- versus AdRR5-transduced pigs (0.59±0.14 versus 0.80±0.19 mm, P=0.02; 0.75±0.21 versus 1.04±0.25 mm, P=0.019; and 53±15% versus 75±11%, P=0.006, respectively). Lumen area was significantly larger (0.70±0.35 mm2 in AdCMVceNOS versus 0.32±0.18 mm2 in AdRR5, P=0.007). Conclusions - Percutaneous adenovirus-mediated NOS gene transfer resulted in efficient local overexpression of functional NOS after angioplasty in coronary arteries. Restored NO production in injured coronary arteries significantly reduced luminal narrowing, most likely through a combined effect on neointima formation and on vessel remodeling after angioplasty.

KW - Genes

KW - Nitric oxide

KW - Remodeling

KW - Restenosis

KW - Vessels

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