Endothelial nitric oxide synthase gene transfer restores endothelium-dependent relaxations and attenuates lesion formation in carotid arteries in apolipoprotein E-deficient mice.
- Mujynya-Ludunge K Division of Cardiology, University of Lausanne, Faculty of Biology and Medicine CHUV-BH10, Lausanne, Switzerland.
- Viswambharan H
- Driscoll R
- Ming XF
- von Segesser LK
- Kappenberger L
- Yang Z
- Vassalli G
- 2004-12-04
Published in:
- Basic research in cardiology. - 2005
Adenoviridae
Animals
Apolipoproteins E
Carotid Artery Diseases
Carotid Artery, Common
Chemokine CCL2
Cholesterol
Cholesterol, HDL
Dietary Fats
Disease Models, Animal
Dose-Response Relationship, Drug
Gene Transfer Techniques
Genetic Therapy
Genetic Vectors
Humans
Macrophages
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Mutation
Nitric Oxide Synthase Type III
Vasodilation
Vasodilator Agents
English
Nitric oxide (NO) and monocyte chemoattractant protein-1 (MCP-1) exert partly opposing effects in vascular biology. NO plays pleiotropic vasoprotective roles including vasodilation and inhibition of platelet aggregation, smooth muscle cell proliferation, and endothelial monocyte adhesion, the last effect being mediated by MCP-1 downregulation. Early stages of arteriosclerosis are associated with reduced NO bioactivity and enhanced MCP-1 expression. We have evaluated adenovirus-mediated gene transfer of human endothelial NO synthase (eNOS) and of a N-terminal deletion (8ND) mutant of the MCP-1 gene that acts as a MCP-1 inhibitor in arteriosclerosis-prone, apolipoprotein E-deficient (ApoE(-/-)) mice. Endothelium-dependent relaxations were impaired in carotid arteries instilled with a noncoding adenoviral vector but were restored by eNOS gene transfer (p < 0.01). A perivascular collar was placed around the common carotid artery to accelerate lesion formation. eNOS gene transfer reduced lesion surface areas, intima/media ratios, and macrophage contents in the media at 5-week follow-up (p < 0.05). In contrast, 8ND-MCP-1 gene transfer did not prevent lesion formation. In conclusion, eNOS gene transfer restores endothelium-dependent vasodilation and inhibits lesion formation in ApoE(-/-) mouse carotids. Further studies are needed to assess whether vasoprotection is maintained at later disease stages and to evaluate the long-term efficacy of eNOS gene therapy for primary arteriosclerosis.
- Language
-
- English
- Open access status
- green
- Identifiers
-
- DOI 10.1007/s00395-004-0500-9
- PMID 15578196
- Persistent URL
- https://sonar.ch/global/documents/189598
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