Sci. Aging Knowl. Environ., 22 January 2003
Antioxidants and arginine cushion vessels from high-speed blood flow
Key Words: endothelium free radicals reactive oxygen species vascular
If rodents could stock up on the latest supplements, mice with high cholesterol might soon be running to health food stores: New results show that adding a protein building block called arginine to an antioxidant-rich diet fights damage. The work also identifies several molecular players that might play a role in atherosclerosis.
When blood flows through vessels, it produces oxygen radicals (see "The Two Faces of Oxygen"). The radicals chemically pervert low density lipoprotein (LDL) cholesterol, which cultivates heart disease with the help of immune cells called macrophages. Macrophages gorge themselves on the corrupted LDL and migrate into the vessel wall. As the gluttons push deeper, they provoke inflammation. The resulting inflammatory debris and cholesterol flotsam form plaques that obstruct blood flow, causing high blood pressure and rendering people vulnerable to heart attacks and strokes.
Plaques originate at blood vessel branches, where the increased turbulence of surging blood amplifies the extent of oxidative stress. Nitric oxide (NO) released by cells in the wall minimizes the blood vessel damage by neutralizing radicals and slowing the migration of macrophages into the vessel wall. But turbulence undermines our hero by killing NO-producing cells. de Nigris and colleagues wanted to know whether restoring NO as well as adding the antioxidant vitamins C and E would help cultured human cells and mice fight radicals.
First, the researchers tested human cells cultured from blood vessel walls. They added vitamins C and E to one culture and the amino acid arginine, which cells convert to NO, to another. They bathed a last culture in vitamins and arginine. The team then measured the amounts of NO synthase, the enzyme that makes NO, in cells subjected to forces equivalent to those produced by vein and artery blood flow. The combination produced more enzyme than the individual treatments did, indicating that arginine improves the cells' ability to respond to the stress of fluid flow.
The team then tested the compounds in a strain of mice that develops atherosclerosis when fed a high-fat diet. After the mice had fattened up for 6 months, the researchers added the vitamins or arginine to the mouse food. A subset of animals also received both concoctions. After 1 and 8 weeks of treatment, the scientists measured the amount of NO synthase in cells that line the vessel walls. In the stress-prone vessels of fortified animals, synthase numbers nearly doubled in animals that enjoyed vitamins plus arginine, whereas vitamins or arginine alone produced only slightly more enzyme than healthy, nonbranched vessels did. The group also measured the production of two proteins--ELK-1 and Creb--that are thought to provoke oxidative stress. Vitamins and arginine curtailed the upsurge of those molecules, suggesting that the dietary enrichments combat stress by reducing quantities of ELK-1 and Creb.
The work "connects the dots between the petri dish and the animal," says pharmacologist David Wink of the National Cancer Institute in Bethesda, Maryland. By identifying key molecular players involved in shear stress in tissue culture and mice, the paper provides mechanistic details of atherosclerotic disease. If the results hold up, mice might not be the only animals scampering to the nutrition store.
F. de Nigris, L. O. Lerman, S. W. Ignarro, G. Sica, A. Lerman, W. Palinski, L. J. Ignarro, C. Napoli, Beneficial effects of antioxidants and L-arginine on oxidation-sensitive gene expression and endothelial NO synthase activity at sites of disturbed shear stress. Proc. Natl. Acad. Sci. U.S.A., 13 January 2003 [e-pub ahead of print]. [Abstract] [Full Text]
January 22, 2003 Citation: M. Beckman, Shear Benefits. Science's SAGE KE (22 January 2003), http://sageke.sciencemag.org/cgi/content/full/sageke;2003/3/nw13
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