Enhanced endothelial adhesiveness in hypercholesterolemia is attenuated by L-arginine

Philip S. Tsao, Leslie M. McEvoy, Helmut Drexler, Eugene C. Butcher, John P. Cooke

Research output: Contribution to journalArticle

290 Scopus citations

Abstract

Background: We have shown that chronic administration of the nitric oxide (NO) precursor L-arginine normalizes NO-dependent vasodilation and markedly inhibits atherogenesis in a hypercholesterolemic rabbit model. We hypothesized that this antiatherogenic effect is due to modulation of endothelial adhesiveness by endothelium-derived NO. Methods and Results: New Zealand White rabbits were fed normal chow (Cont), a high-cholesterol diet (Chol), a high-cholesterol diet supplemented with L-arginine (Arg), or a normal diet supplemented with the NO synthase antagonist L-nitroarginine (L- NA) for 2 weeks. In additional studies, some animals receiving L-NA were also treated with hydralazine to normalize blood pressure. After 2 weeks, thoracic aortas were harvested, opened longitudinally, and placed in a culture dish with the endothelial surface exposed to medium containing WEHI 78/24 cells, a monocytoid cell line. After incubation with the monocytoid cells for 30 minutes on a rocking platform, the aortic segments were washed repeatedly to remove nonadherent cells and adherent cells counted by epifluorescent microscopy. Monocytoid cell binding to aortic endothelium was significantly increased in Chol (P<.001 versus Cont); binding was markedly reduced in arginine-fed hypercholesterolemic animals (P<.05, Arg versus Chol). Monocytoid cell binding to aortic endothelium was also significantly increased in L-NA (P<.05); hydralazine normalized blood pressure but did not reduce monocytoid cell binding. To confirm that alterations in NO activity modulate endothelial cell-monocyte interaction, the release of nitrogen oxides (NO(x)) by thoracic aortas was assessed by a chemiluminescent technique. The concentration of NO(x) in the conditioned medium from segments of Arg thoracic aortas was significantly greater than that from Cont aortas, whereas that from L-NA aortas was significantly less. Conclusions: Hypercholesterolemia enhances the adhesiveness of aortic endothelium for monocytes; this effect is attenuated by dietary L-arginine. Conversely, inhibition of NO synthesis enhances monocyte binding. The results suggest that endothelium-derived NO plays an important role in regulating the endothelial adhesiveness for monocytes. Alterations in NO activity may play a critical role in atherogenesis.

Original languageEnglish (US)
Pages (from-to)2176-2182
Number of pages7
JournalCirculation
Volume89
Issue number5
DOIs
StatePublished - May 1994

Keywords

  • arginine
  • atherosclerosis
  • endothelium-derived factors

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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