Journal
JOURNAL OF VASCULAR RESEARCH
Volume 46, Issue 2, Pages 109-118Publisher
KARGER
DOI: 10.1159/000151444
Keywords
Apoptosis; Gene transfer; Nitric oxide; Oxidative stress; Restenosis
Categories
Funding
- American Heart Association
- National Institutes of Health [HL14388, HL081750]
- NIH [P30 DK54759]
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL081750, P01HL014388] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [P30DK054759] Funding Source: NIH RePORTER
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Objectives: We hypothesized that redox-mediated apoptosis of medial smooth muscle cells (SMC) during the acute phase of vascular injury contributes to the pathophysiology of vascular disease. Methods: Apoptosis of medial SMC (1-14 days following balloon injury) was identified in rat carotid arteries by in situ DNA labeling. NADPH-derived superoxide and expression of Bcl-xL, Bax, caspase-3 and caspase-9 were assessed. The antioxidant tempol was administered in drinking water throughout the experimental period, and local adenoviral-mediated gene transfer of eNOS was performed prior to vascular injury. Results: Balloon injury increased NADPH-dependent superoxide production, medial SMC apoptosis, Bax-positive medial SMC index, Bax/Bcl-xL ratio, and caspase-3 and caspase-9 expression in the injured arteries. Treatment with tempol or eNOS gene transfer decreased superoxide levels and medial SMC apoptosis, with a concomitant increase in medial SMC density. Inhibition of superoxide was associated with a decreased Bax/Bcl-xL ratio, and caspase-3 and -9 expression. Tempol treatment and eNOS gene therapy significantly reduced neointima formation. Conclusion: Vascular generation of reactive oxygen species participates in Bax activation and medial SMC apoptosis. These effects likely contribute to the shedding of cell-cell adhesion molecules and promote medial SMC migration and proliferation responsible for neointimal hyperplasia. Copyright (C) 2008 S. Karger AG, Basel
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