Sci. Aging Knowl. Environ., 12 February 2003
Vol. 2003, Issue 6, p. nw27
[DOI: 10.1126/sageke.2003.6.nw27]


Acing the Stress Test

Life-extending genetic alteration prevents artery damage

Kate Ramsayer;2003/6/nw27

Key Words: atherogenesis • hypercholesterolemia • isoprostanes

A yoga session or a walk in the park relieves emotional stress, which can keep a heart healthy. Genetic tricks that temper a different kind of stress also protect the ticker, according to new work: Mutant mice that live long by repelling oxidative damage resist the early stages of clogged arteries. The study reveals a molecular connection between aging and atherosclerosis, and it pinpoints a possible target for future heart-preserving therapies.

Atherosclerosis develops when immune cells called macrophages gobble cholesterol and form fatty lesions in blood vessels. Macrophages consume cholesterol that's been battered by destructive forms of oxygen known as reactive oxygen species (ROS). The effects of oxidative damage extend beyond the heart; many researchers believe that they contribute to the aging process as well (see "The Two Faces of Oxygen"). For instance, mice that lack a protein called p66shc live 30% longer than their normal siblings do, possibly because their cells are less likely to commit suicide in response to oxidative assault (see "Stay Mellow, Stay Young"). Molecular biologist Claudio Napoli of the University of Naples in Italy and colleagues wondered whether the molecule's absence would also repugn heart disease.

To address this question, the researchers fed a high-fat diet to normal mice and to animals that lack p66shc. Then they examined the rodents' aortas for damage. Normal animals showed early signs of heart disease: Lesions covered 21% more of the vessel walls of fat-fed mice than those of rodents on a regular diet. The absence of p66shc protected mice, however. Mutant animals on a high-fat diet showed only a 3% increase in blood vessel damage over that in their compatriots who ate leaner fare.

Additional experiments reveal that mice without p66shc seemed to resist oxidative damage induced by the unhealthy diet. Compared to genetically normal mice, the mutant rodents showed fewer molecular indicators of oxidative stress in their blood vessels, including smaller amounts of oxidized cholesterol. In addition, the researchers observed reduced numbers of cholesterol-swamped macrophage cells and fewer aorta cells that had committed suicide, a typical response to oxidative damage. Together, the results suggest that the absence of p66shc helps mice resist the first steps of atherosclerosis. Next, Napoli wants to test whether p66shc influences later stages of coronary disease and to assess whether p66shc fosters human heart disease.

The study "places p66shc as a central player in regulating the amount of oxidative stress in the vessel wall, which is very important for atherosclerosis formation," says molecular biologist Toren Finkel of the National Heart, Lung, and Blood Institute in Bethesda, Maryland. Blocking p66shc with drugs might squelch the atherosclerosis-promoting actions of oxidative stress, he says, although no one has identified inhibitors of the protein. The research "begins to tie together the importance of ROS in both the process of aging and of atherosclerosis," says cell biologist Daniel Steinberg of the University of California, San Diego. Future studies could reveal new paths to a cellular state of Zen that brings long life and a healthy heart.

--Kate Ramsayer

February 12, 2003
  1. C. Napoli et al., Deletion of the p66Shc longevity gene reduces systemic and tissue oxidative stress, vascular cell apoptosis, and early atherogenesis in mice fed a high-fat diet. Proc. Natl. Acad. Sci. U.S.A., 5 February 2003 [e-pub ahead of print]. [Abstract] [Full Text]
Citation: K. Ramsayer, Acing the Stress Test. Sci. SAGE KE 2003 (6), nw27 (2003).

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