Gene transfer of endothelial nitric oxide synthase alters endothelium- dependent relaxations in aortas from diabetic rabbits

M. Zanetti, J. Sato, Zvonimir S Katusic, T. O'Brien

Research output: Contribution to journalArticle

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Abstract

Aims/hypothesis. Cardiovascular disease is the leading cause of death in diabetes mellitus. Abnormal endothelium-dependent relaxation is observed both in humans and in animal models of diabetes mellitus and decreased bioavailability of nitric oxide (NO) is thought to be involved in this defect. Therefore, the aim of this study was to test whether adenovirus- mediated gene transfer of endothelial nitric oxide synthase (eNOS) alters vascular reactivity of diabetic vessels. Methods. Vascular reactivity was first assessed in thoracic aortas and carotid arteries from nine alloxan- induced diabetic (plasma glucose, 26.5 ± 1.2 mmol/l; HbA(1c), 6.4 ± 0.3%) and nine control rabbits (plasma glucose, 11.1 ± 1.3 mmol/l; HbA(1c), 2.1 ± 0.1%). Vascular reactivity was next examined in thoracic aortas of diabetic animals after ex vivo transduction with replication-deficient adenovirus encoding gene for eNOS (AdeNOS) or β-galactosidase (Adβgal). Results. After 10 weeks of hyperglycaemia, endothelium-dependent relaxation to acetylcholine was impaired in diabetic aorta, but was normal in carotid arteries from diabetic rabbits. In contrast, responses of both vessels to calcium ionophore and nitric oxide donor were normal. Histochemical staining for β- galactosidase and immunohistochemistry for eNOS showed transgene expression in the endothelium and adventitia in Adβgal and AdeNOS transduced vessels, respectively. During submaximum contractions with phenylephrine, relaxations to low concentrations of acetylcholine (3 x 10-8 to 10-7 mol/l) were augmented in AdeNOS transduced diabetic vessels. Conclusion/interpretation. These findings suggest that adenovirus-mediated gene transfer of eNOS to diabetic aorta alters vascular reactivity.

Original languageEnglish (US)
Pages (from-to)340-347
Number of pages8
JournalDiabetologia
Volume43
Issue number3
StatePublished - 2000

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Nitric Oxide Synthase Type III
Adenoviridae
Endothelium
Aorta
Galactosidases
Blood Vessels
Rabbits
Genes
Thoracic Aorta
Carotid Arteries
Acetylcholine
Diabetes Mellitus
Thoracic Arteries
Glucose
Adventitia
Alloxan
Nitric Oxide Donors
Calcium Ionophores
Phenylephrine
Transgenes

Keywords

  • Adenovirus
  • Alloxan
  • Diabetes mellitus
  • Endothelium
  • Gene transfer
  • Nitric oxide
  • Nitric oxide synthase

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Gene transfer of endothelial nitric oxide synthase alters endothelium- dependent relaxations in aortas from diabetic rabbits. / Zanetti, M.; Sato, J.; Katusic, Zvonimir S; O'Brien, T.

In: Diabetologia, Vol. 43, No. 3, 2000, p. 340-347.

Research output: Contribution to journalArticle

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abstract = "Aims/hypothesis. Cardiovascular disease is the leading cause of death in diabetes mellitus. Abnormal endothelium-dependent relaxation is observed both in humans and in animal models of diabetes mellitus and decreased bioavailability of nitric oxide (NO) is thought to be involved in this defect. Therefore, the aim of this study was to test whether adenovirus- mediated gene transfer of endothelial nitric oxide synthase (eNOS) alters vascular reactivity of diabetic vessels. Methods. Vascular reactivity was first assessed in thoracic aortas and carotid arteries from nine alloxan- induced diabetic (plasma glucose, 26.5 ± 1.2 mmol/l; HbA(1c), 6.4 ± 0.3{\%}) and nine control rabbits (plasma glucose, 11.1 ± 1.3 mmol/l; HbA(1c), 2.1 ± 0.1{\%}). Vascular reactivity was next examined in thoracic aortas of diabetic animals after ex vivo transduction with replication-deficient adenovirus encoding gene for eNOS (AdeNOS) or β-galactosidase (Adβgal). Results. After 10 weeks of hyperglycaemia, endothelium-dependent relaxation to acetylcholine was impaired in diabetic aorta, but was normal in carotid arteries from diabetic rabbits. In contrast, responses of both vessels to calcium ionophore and nitric oxide donor were normal. Histochemical staining for β- galactosidase and immunohistochemistry for eNOS showed transgene expression in the endothelium and adventitia in Adβgal and AdeNOS transduced vessels, respectively. During submaximum contractions with phenylephrine, relaxations to low concentrations of acetylcholine (3 x 10-8 to 10-7 mol/l) were augmented in AdeNOS transduced diabetic vessels. Conclusion/interpretation. These findings suggest that adenovirus-mediated gene transfer of eNOS to diabetic aorta alters vascular reactivity.",
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