The heat that hurts  pg. 4

As foam cells within a lesion die, the center of the plaque becomes necrotic, weakening the overlying fibrous cap and increasing the risk of rupture. The interior of an atherosclerotic plaque contains molecules that attract platelets and provide ample sites for attachment.

Thus, when an atherosclerotic plaque ruptures, a clot can quickly form and completely occlude the blood vessel. Acute cardiovascular events are most often precipitated by the rupture of the thin fibrous cap that covers the atherosclerotic plaque.

Clot blocker

Aspirin, the classic anti-inflammatory drug, can prevent clot formation over atherosclerotic plaques by inhibiting the enzyme cycoloxygenase-1 (COX-1) in platelets. That, in turn, reduces formation of the prostaglandin Thromboxane A2 (TxA2), a powerful pro-coagulant molecule.

Aspirin also inhibits the related COX-2 enzyme, which produces other pro-inflammatory prostaglandins at sites of inflammation. Long recognized for its role in chronic inflammatory processes like arthritis, COX-2 is also expressed by cells within atherosclerotic plaques, but not elsewhere in the circulatory system.

Linton and Fazio have reported that COX-2 contributes to the pathology of atherosclerosis in mouse models of the disease. Inhibiting the enzyme in mice with high cholesterol levels, either pharmacologically or genetically, retards early atherosclerotic plaque formation. These data suggest that blocking inflammation could suppress the progression of atherosclerosis.

But Linton cautions that the tale is not so cut-and-dry. “It’s tough to say (whether COX-2) is just good or bad. It probably depends on which cell is expressing it and at what time.” For example, “COX-2 is expressed by basically all the players in the artery wall—smooth muscle cells, endothelial cells, macrophages,” he says.

In addition, macrophages down-regulate their pro-inflammatory activities and lose COX-2 expression when they become foam cells. Other studies have suggested that blocking COX-2 activity does little to ameliorate the symptoms of more advanced atherosclerotic lesions.

This change in macrophage gene expression may come out of necessity: “When it’s overloaded with cholesterol, the macrophage has to focus on getting rid of cholesterol,” Linton explains. “Before that, it may be more important to be an inflammatory cell involved in the recruitment of other cells and propagation of the inflammatory pathway.”

Experiments on atherosclerotic mice have provided significant insight into the mechanisms behind cardiovascular disease, including the recent findings on the role of inflammation. Even so, Fazio is quick to point out that the mouse models of atherosclerosis offer only a pale reflection of the disease state in human beings.

“There is an issue in quality and in the extent and topography (of lesions in mice),” Fazio cautions. The majority of human cases of atherosclerosis, according to Fazio, are due to a combination of risk factors. This is in sharp contrast to atherosclerosis in mice induced experimentally by the targeted disruption of one or two genes.

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