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


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.
Kuhlencordt
Peter J
PJ
Medizinische Klinik, University Wuerzburg, Germany. kuhlencord_p@klink.uni-wuerzburg.de
Hötten
Stefanie
S
Schödel
Johannes
J
Rützel
Sebastian
S
Hu
Kai
K
Widder
Julian
J
Marx
Alexander
A
Huang
Paul L
PL
Ertl
Georg
G
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency*; D050197:Atherosclerosis / Q000517:prevention & control*; D001794:Blood Pressure; D001808:Blood Vessels / Q000201:enzymology; D004274:DNA, Recombinant; D005091:Exons; D005260:Female; D014644:Genetic Variation; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052248:Nitric Oxide Synthase Type I / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D013194:Staining and Labeling; D017539:Tunica Intima / Q000201:enzymology
D001057:Apolipoproteins E; D004274:DNA, Recombinant; D052248:Nitric Oxide Synthase Type I