(Circulation. 1995;92:898-903.)
© 1995 American Heart Association, Inc.
Articles |
Dietary Correction of Hypercholesterolemia in the Rabbit Normalizes Endothelial Superoxide Anion Production
From the Divisions of Cardiology (Y.O., T.E.P., H.S.S., D.G.H.) and Hematology/Oncology (R.R.S., J.N.W.), Emory University School of Medicine, and the Atlanta Veterans Administration Medical Center (D.G.H.), Atlanta, Ga.
Correspondence to David G. Harrison, MD, Cardiology Division, PO Box Drawer LL, Emory University School of Medicine, Atlanta, GA 30322.
Background We have shown that hypercholesterolemia increases vascular superoxide anion (O2-) production, which could be responsible for augmented inactivation of endothelium-derived vascular relaxing factor. We sought to determine whether this increased vascular O2- production is due to infiltration of macrophages into the intima and whether dietary treatment of hypercholesterolemia normalizes O2- production.
Methods and Results A specific and sensitive assay for O2- based on chemiluminescence of lucigenin was used; the amount of O2- produced by vascular ring segments was quantified based on known quantities of O2- produced by xanthine–xanthine oxidase standards. O2- production of aortic segments from normal rabbits (n=9), cholesterol-fed rabbits (1% cholesterol diet for 1 month, n=7), and rabbits fed a 1% cholesterol diet for 1 month followed by a normal diet for 1 month (regression rabbits, n=5) was measured. At the end of these diets, serum cholesterol levels were 1.5±0.2, 26.0±3.9, and 1.8±0.5 mmol/L (58±6, 1000±150, and 71±19 mg/dL) in the normal, cholesterol-fed, and regression animals, respectively. Vessels from normal rabbits with endothelium produced 0.32±0.06 nmol O2-/mg dry wt per minute, whereas those without endothelium produced approximately twice as much O2- (0.66±0.12 nmol O2- mg dry wt per minute. Vessels with endothelium from cholesterol-fed rabbits produced 4.5-fold more O2- than vessels from normal animals. This increased production of O2- was normalized by endothelial removal. This increased production of O2- was not due to infiltration of macrophages in the intima, because there was no correlation between vascular O2- production and macrophage infiltration assessed by immunohistochemistry with use of a specific antibody against rabbit macrophage. O2- production by vessels from regression rabbits was similar to that observed in normal animals, and as in the normal rabbits, endothelial removal increased O2- production. Aortic rings from these animals also were studied in organ chambers. Dietary lowering of cholesterol dramatically improved vasodilator responses to acetylcholine and A23187 (P<.05 versus cholesterol-fed rabbits).
Conclusions Dietary lowering of cholesterol not only improves endothelium-dependent vascular relaxation but also normalizes endothelial O2- production. Decreases of O2- production by dietary lowering of cholesterol not only may improve vasomotor control but also may improve other aspects of vascular integrity in atherosclerosis.
Key Words: hypercholesterolemia • macrophages • free radicals • endothelium-derived factors • vasodilation
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