Sci. Aging Knowl. Environ., 22 September 2004
Yin and Yang
Inflammatory molecules fight and foster atherosclerosis
The circulatory system sends mixed messages when it faces atherosclerosis. Cells exude one compound that inhibits fatty buildup in arteries and another molecule that promotes it, according to a new study. Adjusting the proportions of the two molecules might check the obstructions that can lead to heart attacks and strokes.
Patients with atherosclerosis pump out extra amounts of the compounds thromboxane and prostacyclin. Thromboxane comes from platelets, cell fragments that clump to help form a blood clot. The molecule apparently contributes to atherosclerosis: It restricts blood flow by narrowing arteries and encouraging clot formation. Produced by cells in artery walls, prostacyclin expands blood vessels and impedes platelets. But not all studies support the molecules' opposing tendencies. For example, thromboxane-thwarting drugs don't always prevent atherosclerosis in mice; tying up prostacyclin doesn't always promote the disease, says molecular pharmacologist Shuh Narumiya of Kyoto University in Japan. One reason the studies weren't decisive is that the drugs interfere with other molecules besides thromboxane and prostacyclin, making it hard to tease out each one's effects, he says.
Narumiya and colleagues sidestepped that problem by producing atherosclerosis-prone rodents that lacked the receptor for either thromboxane or prostacyclin. In 20-week-old mice, blood vessel lesions were 45% larger in the rodents missing the prostacyclin receptor than in controls. At the same age, mice without the thromboxane receptor carried 70% less plaque than did controls. The researchers also gauged the abundance of endothelial cells in the animals' artery walls. These cells, which cover the lipid accumulations, declined in the group missing the prostacyclin receptor. Their depletion could weaken the plaque, causing it to burst and possibly triggering a heart attack or stroke.
The team also measured quantities of a molecule on the surface of platelets that reflects their stickiness. Priming platelets with a clot-inducing compound boosted quantities of this molecule in controls and animals without the prostacyclin receptor, but not in mice missing the thromboxane receptor. The finding suggests that platelets in prostacyclin-impaired rodents are unusually likely to form a blood clot that can plug an artery. Overall, the study bolsters researchers' suspicions that thromboxane speeds atherosclerosis and prostacyclin slows it. Mice missing the prostacyclin receptor amassed large plaques at a young age, suggesting that prostacyclin hinders the early stages of fat accumulation, says Narumiya. Drugs that prod the prostacyclin receptor or undercut the one for thromboxane might fend off clogged arteries, he says.
"It's important work," says pharmacologist Garret FitzGerald of the University of Pennsylvania in Philadelphia. Drugs such as Celebrex and Vioxx ease arthritis pain by inhibiting an enzyme called COX-2, but COX-2 helps produce prostacyclin. The work heightens concerns that "the inhibitors could have a negative impact on atherosclerosis," he says. Cardiovascular pharmacologist Sandra Pfister of the Medical College of Wisconsin in Milwaukee says, "This is a good step forward that goes further than the pharmacological studies" by revealing details of how prostacyclin and thromboxane help or hinder atherosclerosis. Adjusting the balance between these two molecules might send a clear signal to plaques to stay away.
September 22, 2004
Science of Aging Knowledge Environment. ISSN 1539-6150