Now here's a revolutionary breakthrough: the discovery of the free lunch.

At least from an atherosclerosis point of view. In research published in the March 2005 issue of Cell Metabolism, researchers from the University of Texas Southwestern Medical Center in Dallas report on cell biology results that suggest a novel target for fighting atherosclerosis: apoptosis inhibitor expressed by macrophages, or AIM.

Atherosclerosis, or hardening of the arteries by plaque buildup, is a contributing factor in cardiovascular disease. High levels of oxidized LDL cholesterol are known to be a strong contributing factor to atherosclerotic development, and the level of that cholesterol is more or less a numbers game, depending on the total level of LDL cholesterol.

"The only way we have right now of regulating oxidized LDL cholesterol is to reduce cholesterol overall," which can be achieved by reducing dietary fat levels, as well as through medications, senior author Toru Miyazaki, associate professor at the University of Texas Southwestern Medical Center, told BioWorld Today. "But if the AIM strategy works, we do not need to care about cholesterol level."

In the paper, Miyazaki and his colleagues at UT Southwestern and the University of California at Los Angeles show that partly is due to the fact that oxidized LDL cholesterol promotes the survival of fat-filled "foam" macrophages by up-regulating the production of the anti-apoptotic molecule AIM. Those foam macrophages, in turn, deposit in atherosclerotic plaques, where they contribute to the development and expansion of the plaques. Such plaques reduce blood flow, and, in the later stages of atherosclerosis, also can cause blood clots if they detach from the blood vessels.

"Scavenging oxidized LDL [cholesterol] is one of macrophages' main jobs. In general, they need to eat a lot of bad things," Miyazaki said. "So they need to be very tough."

One of the ways macrophages achieve that toughness is by making AIM, which inhibits apoptosis even when the macrophages accumulate high levels of toxins. The resistance to apoptosis allows them to survive and function despite their nasty diet. The same resistance, however, is what causes the macrophages to accumulate in atherosclerotic lesions as foam cells. In that sense, of course, the body gets no free lunch; what is good for the macrophages is bad for the organism as a whole.

The scientists tested the effects of manipulating AIM levels in mice that already were knockouts for the LDL receptor. "Normal mice will not develop atherosclerosis, even when they are fed a high-fat diet," Miyazaki explained. Mice lacking the LDL receptor, however, will develop atherosclerosis, which enabled the researchers to investigate the effects of AIM in double knockouts.

The scientists induced AIM expression by feeding mice either normal lab chow, high-fat chow or normal chow spiked with an agonist of the LXR receptor, another receptor in macrophages that promotes AIM expression. They found that after a few weeks of that diet, AIM expression was greatly increased in liver macrophages, confirming the results of cell culture experiments. Genetically engineered mice that do not express AIM did not show the staining, ruling out the possibility of nonspecific staining.

They next tested whether the expression of AIM actually protected the macrophages from apoptosis in response to oxidized LDL cholesterol, as it was known to do for bacterial toxins. In both isolated macrophages and animals, knocking out the AIM protein led to greater amounts of apoptotic cells in response to oxidized LDL cholesterol.

In a final set of experiments, the scientists tested whether the long-lived macrophages actually contributed to the development of atherosclerotic disease. They found that while the LDL receptor only and AIM/LDL receptor double knockouts had similar serum cholesterol levels after a few weeks of high-fat food, the double knockouts developed noticeably fewer atherosclerotic lesions.

Since macrophages release pro-inflammatory molecules, which in turn contribute to atherosclerotic pathogenesis, the scientists tested whether the expression of AIM also reduced inflammation. While knocking out AIM had no direct effect on the expression of pro-inflammatory genes in macrophages themselves, it did decrease the expression in blood vessels, simply because fewer AIM knockout cells survived to release such pro-inflammatory molecules.

Miyazaki's group hopes to ultimately apply their findings in clinical settings; for that, it would be necessary to develop specific AIM inhibitors, either antibodies or small molecules. One thing that makes him optimistic about the prospects for AIM inhibition in the clinic is the phenotype of the AIM knockouts - they have none.

"They don't really have a significant phenotype," he said. "They grow normally, reproduce normally, everything."

Of course, given that macrophages have an important immunological role, inducing mass suicide likely would turn out to have side effects of some kind. In their manuscript, the authors do note that their findings are applicable only to early stage atherosclerosis; other research suggests that certain processes might make AIM down-regulation a bad idea in later-stage atherosclerosis, because it could decrease plaque stability, making thrombosis more likely.