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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:1539.)
© 2006 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Atheroprotective Effects of Neuronal Nitric Oxide Synthase in Apolipoprotein E Knockout Mice

Peter J. Kuhlencordt; Stefanie Hötten; Johannes Schödel; Sebastian Rützel; Kai Hu; Julian Widder; Alexander Marx; Paul L. Huang; Georg Ertl

From Medizinische Klinik I (P.J.K., S.H., J.S., S.R., K.H., J.W., G.E.), Cardiovascular Center and Department of Pathology (A.M.), University Wuerzburg, Germany; Division of Cardiology (P.L.H.), Massachusetts General Hospital and Harvard Medical School, Boston, Mass.

Correspondence to Peter J. Kuhlencordt, MD, University Hospital Wuerzburg, Department of Medicine, Josef Schneider Str. 2, D97080 Wuerzburg, Germany. E-mail kuhlencord_p{at}klink.uni-wuerzburg.de

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/nNOS 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 nNOS was present in vessels of KO and absent in DKO animals, nNOS was expressed in KO and DKO mice.

Conclusion— nNOS protects against atherosclerosis as nNOS deletion leads to an increase in plaque formation in apoE/nNOS 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 nNOS 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.

Here we test whether neuronal NOS (nNOS) deficiency affects atherosclerosis in apoE/nNOS double knockout (DKO) and apoE knockout animals. Male and female DKO animals showed a significant increase in lesion-area. Thus, nNOS protects against atherosclerosis. Female but not male DKO mice showed a significant reduction in mean arterial blood pressure.

Key Words: nitric oxide • nitric oxide synthase • arteriosclerosis • blood pressure • gene expression

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Beneficial Effects of Neuronal Nitric Oxide Synthase in Atherosclerosis

Charles J. Lowenstein
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