Atheroprotective effects of neuronal nitric oxide synthase in apolipoprotein e knockout mice.

Abstract

OBJECTIVE:

All 3 isoforms of the nitric oxide synthase (NOS) are expressed in atherosclerotic lesions. To test whether neuronal NOS (nNOS) deficiency affects atherosclerosis, we studied apoE/nNOSalpha double knockout (DKO) and apolipoprotein E (apoE) knockout (KO) control mice.

METHODS AND RESULTS:

Lesion area was significantly increased in male DKO (66%) mice after 14 weeks and in female DKO animals (31%) after 24 weeks of "western" diet. Moreover, mean arterial blood pressure was significantly reduced in female DKO animals. Immunohistochemistry revealed nNOS expression in the neointima of KO mice. In DKO animals, residual nNOS staining was caused by the presence of nNOS splice variants. Whereas nNOSalpha was present in vessels of KO and absent in DKO animals, nNOSgamma was expressed in KO and DKO mice.

CONCLUSIONS:

nNOSalpha protects against atherosclerosis as nNOSalpha deletion leads to an increase in plaque formation in apoE/nNOSalpha DKO mice. Female DKO mice showed a significant reduction in mean arterial blood pressure. Additionally, we found expression of nNOS splice variants in vessels of apoE KO mice. Our data highlights nNOSalpha overexpression as a potential therapeutic strategy and naturally occurring splice variants that lack exon 2 of the nNOS gene as a potential risk factor for vascular disease.

• Authors: Peter J Kuhlencordt, Stefanie Hötten, Johannes Schödel, Sebastian Rützel, Kai Hu, Julian Widder, Alexander Marx, Paul L Huang, Georg Ertl
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 26 Issue 7 Pg. 1539-44 (Jul 2006) ISSN: 1524-4636 [Electronic] United States
• PMID: 16627802 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Apolipoproteins E
• DNA, Recombinant
• Nitric Oxide Synthase Type I

Topics

• Animals
• Apolipoproteins E (deficiency)
• Atherosclerosis (prevention & control)
• Blood Pressure
• Blood Vessels (enzymology)
• DNA, Recombinant
• Exons
• Female
• Genetic Variation
• Immunohistochemistry (methods)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Nitric Oxide Synthase Type I (genetics, metabolism, physiology)
• Staining and Labeling
• Tunica Intima (enzymology)