Regulation of endothelial nitric oxide synthase expression in the vascular wall and in mononuclear cells from hypercholesterolemic rabbits.
BACKGROUND
We recently obtained evidence demonstrating that cultured bovine endothelial cells contain cytosolic proteins that form complexes with the 3'-untranslated region of endothelial nitric oxide synthase (eNOS) mRNA and are associated with its destabilization. The aim of this study was to determine the presence of such proteins and eNOS expression in hypercholesterolemic rabbits as an in vivo model of endothelial dysfunction.


RESULTS
Endothelium-dependent relaxation to acetylcholine and the calcium ionophore A23187 was reduced in aortic segments from hypercholesterolemic rabbits compared with controls. Treatment of hypercholesterolemic rabbits with cerivastatin (0.1 mg. kg body wt(-1). d(-1)) restored endothelium-dependent relaxation. Aortic eNOS expression was reduced in hypercholesterolemic rabbits and was accompanied by enhanced binding activity of a 60-kDa cytosolic protein and reduced stability of eNOS mRNA. Cerivastatin treatment upregulated eNOS expression and reduced the interaction of the cytosolic protein with the 3'-untranslated region of eNOS mRNA. Mononuclear cells from hypercholesterolemic rabbits also showed a marked reduction of eNOS expression and eNOS mRNA stability and an increase in binding activity of the cytosolic protein, which were also prevented by cerivastatin treatment.


CONCLUSIONS
These results demonstrate the presence of a 60-kDa protein that binds to eNOS mRNA and reductions in eNOS expression in both vascular wall and mononuclear cells that are prevented by cerivastatin.
Jiménez
A
A
Fundación Jiménez Díaz, Cardiovascular Research and Hypertension Laboratory, Madrid, Spain.
Arriero
M M
MM
López-Blaya
A
A
González-Fernandez
F
F
García
R
R
Fortes
J
J
Millás
I
I
Velasco
S
S
Sánchez De Miguel
L
L
Rico
L
L
Farré
J
J
Casado
S
S
López-Farré
A
A
D020413:3' Untranslated Regions / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000503:physiopathology; D003600:Cytosol / Q000378:metabolism; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology; D005786:Gene Expression Regulation / Q000187:drug effects; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D006937:Hypercholesterolemia / Q000188:drug therapy / Q000503:physiopathology*; D066298:In Vitro Techniques; D007476:Ionophores / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D046911:Macromolecular Substances; D008297:Male; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III; D011485:Protein Binding / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology*; D020871:RNA Stability / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D011817:Rabbits; D013379:Substrate Specificity; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
D020413:3' Untranslated Regions; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007476:Ionophores; D046911:Macromolecular Substances; D011725:Pyridines; D012333:RNA, Messenger; D014665:Vasodilator Agents; C086276:cerivastatin; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III