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Gene may protect against heart disease rather than be harmful as previously thought

28.11.2003


A genetic pathway whose activity was suspected to advance heart disease by increasing inflammation in the blood vessels and arteries feeding the heart may actually protect against it at least in laboratory mice, reports a team of Rockefeller University scientists led by Jan Breslow, M.D., in the Nov. 25 issue of Proceedings of the National Academy of Sciences.



The Rockefeller scientists’ findings that blocking the NFkB pathway actually contributes to heart disease in the lab animals, occurred as part of their larger study to identify mechanisms of heart disease that are unrelated to one of the primary risk factors for the disease: high blood levels of "bad" cholesterol and low levels of "good" cholesterol.

"Having high cholesterol increases your risk, but does not mean that you will get heart disease," explains Susanne Idel, Ph.D., the Rockefeller scientist who is the lead author of the PNAS paper. "There are people who smoke, who are overweight, or who eat badly, and whose blood vessels and arteries don’t become obstructed by the fatty build-up called plaques.


"So, there must be genetic pathways other than those connected to cholesterol metabolism. Our research has identified a non-cholesterol related gene that is linked to the development of heart disease in mice."

Understanding the actions of the NFkB (Nuclear Factor Kappa-B) pathway may suggest new treatment approaches against heart disease, the number one killer of adult men and women in the United States.

"Right now, the main ways we have to prevent heart disease relate to cholesterol, blood pressure and other risk factors for heart attack," says Idel. "In the long term, our hope is that we will have a more complex understanding of the genetics involved that gives us new tools for treating heart disease."

In the recent study, Idel, Breslow and co-author Hayes M. Dansky, M.D. (Cardiovascular Institute, Mt. Sinai School of Medicine) focused on the NFkB pathway and the A20 gene that regulates this pathway. NFkB, a protein that controls the inflammatory response, is activated as part of the body’s natural response to the fatty streaks that accumulate in the blood vessels and arteries as the first stage of heart disease. The inflammatory response is not exclusive to these fatty streaks, also called atherosclerotic plaques, but is generally activated when tissue is damaged by harmful agents such as viruses, bacteria, chemicals or physical trauma. In response to the inflammation, the tissue lining the blood vessels and arteries change in ways associated with inflammation. The mechanism of NFkB regulation by A20 is not related to any of the known cholesterol pathways.

Because the NFkB pathway turns on inflammatory genes and inflammation is associated with atherosclerosis, some scientists have focused on this pathway as one route that promotes heart disease. But mounting evidence suggests that the reverse may be true. Several research groups have created mice in which the pathway has been disabled and the animals’ blood vessels and arteries have actually less atherosclerosis.

"The idea that NFkB has an anti-atherosclerotic effect is controversial," says Idel. "But, if it were true that the pathway had only harmful effects, then turning it off should have protected the mice. This is not what we have observed."

"NFkB does turn on inflammatory genes," continues Idel, "but you can’t disregard that it also turns on other genes that may be important for cell survival. It regulates genes that promote anti-inflammatory and anti-cell death mechanisms. These other genes are important, too, and they may have a protective effect. Thus it might be beneficial if the NFkB pathway remains active longer for its anti-inflammatory and anti-cell death related effects."

Substantiating this view are findings from the Breslow lab published in the PNAS paper. The scientists discovered that two strains of mice exhibit genetic differences in the A20 gene, which cause them to shut down the NFkB pathway at different speeds. Mice that turn off NFkB less efficiently have less severe atherosclerosis.

The Breslow team’s track record in heart disease research is extensive. For example, the lab pioneered the mouse model of heart disease, thereby providing the scientific community with a non-human animal to study disease genetics in a controlled fashion that can render discoveries relevant for the human condition. Atherosclerosis does not normally occur in mice, but was modeled for the first time in the mouse by the Breslow team by knocking out, or deleting, a gene called Apo E. These mice are known as Apo E knockout mice.

The severity of atherosclerotic disease is seen in varying degrees among different strains of Apo E knockout mice. Genetic differences cause them to have different ranges of disease as indicated by the size of the fatty lesions in the blood vessels and arteries.

In a prior study, the Breslow group compared the genetic make-up of two strains of Apo E knockout mice whose atherosclerotic fatty obstructions differed in degree of severity. They were searching for stretches of DNA that some mice with less severe lesions had inherited in common. From this study, they identified a locus, or area in the mouse genome, linked to the size of atherosclerotic lesions. With other variables controlled for, the mice with one version of the locus would get two times as much atherosclerosis as the mice with the other version. The study’s authors concluded that some variation in the genes at this locus must cause the observed athero-protective effect.

The Breslow team identified A20 as a candidate gene for the athero-related observations for three reasons. First, it is within the locus of interest, located on chromosome 10. Second, it regulates NFkB. Third, and this part is key, its basic structure in the athero-protected mice differs slightly from the A20 in the athero-prone mice. The two versions differ by one amino acid. This is called a point mutation.

Genetic mutations can be "silent" when they have no effect, but in this case, the variation has a demonstrable effect. The A20 proteins produced have slightly different structures and they demonstrate different regulation patterns. As result, NFkB remains active for different amounts of time in the two strains of mice.

The scientists believe A20 works this way. NkB turns A20 on. Once A20 becomes activated, it turns NFkB off, thereby stopping the process of its own activation. This is called feedback inhibition. But, the version of A20 correlated with reduced atherosclerosis turns NFkB off less effectively. As a result, NFkB remains active longer and targets of NFkB, the genes it activates, also demonstrate prolonged activity. In light of the previous study, prolonged NFkB activity in mice is linked with reduced atherosclerosis.

The studies authors are careful to say that while their results are interesting, the NFkB story is incomplete.

"The NFkB pathway turns on some genes that would be expected to ameliorate atherosclerosis and some genes that make it worse," says Idel. "In the mice, an active pathway seems to be preferable, but more research is required to determine how the effects balance out. There is still much that is unknown about the genetics of heart disease, but A20 and the NFkB pathway offer promising leads worthy of more study."


This research was supported in part by grants from the National Institutes of Health and the German Academic Exchange Service.

Joseph Bonner | EurekAlert!
Further information:
http://www.rockefeller.edu/

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