An experiment that turned out very differently than expected led scientists at Washington University School of Medicine
in St. Louis to the first direct link between inefficient metabolism and atherosclerosis.
"For years, we've heard people say, 'Bad metabolism runs in my family,'" says Clay F. Semenkovich, M.D., professor of
medicine and of cell biology and physiology. "Our study suggests 'bad' metabolism does lead to inflammation in blood vessel
walls and can contribute to heart attacks and strokes."
Smoking and elevated cholesterol levels have been shown to increase vascular disease, but these risk factors are absent in
many cases. Reporting this week in the journal Nature, Semenkovich and colleagues offer evidence of another mechanism behind
atherosclerosis. Traditionally, scientists have thought of atherosclerosis as a chronic inflammation that results from
vascular injury. But these studies suggest the root cause may be mitochondrial problems in the cells of the blood vessel
wall. Semenkovich says the findings provide scientists with new targets for treating vascular disease.
The researchers studied mice genetically engineered to overproduce a protein in the wall of the aorta, the body's primary
artery. When made in skeletal muscle, the protein, called uncoupling protein-1, protects mice from diabetes and obesity.
Uncoupling protein converts the energy from food into heat and, in skeletal muscle, mimics the effects of exercise.
The researchers thought if the mice made uncoupling protein-1 in their blood vessel walls, it might protect them from
atherosclerosis and high blood pressure.
"Our original hypothesis was wrong," says Semenkovich, who directs the School of Medicine's Division of Endocrinology,
Metabolism and Lipid Research and is a staff physician at Barnes-Jewish Hospital. "When we made mice that produced uncoupling
protein in the aorta, we were amazed because rather than being protected from damage, they developed high blood pressure and
atherosclerosis." Semenkovich and co-first authors Carlos Bernal-Mizrachi, M.D., instructor of medicine, and Allison Gates,
Ph.D., a postdoctoral fellow, turned on the manufacture of uncoupling protein-1 by giving the mice the antibiotic doxycycline
in their drinking water. Mice treated with doxycycline developed atherosclerosis more frequently than untreated littermates.
Other than the presence of uncoupling protein in the aorta, all mice used in the experiments had the same cholesterol levels,
glucose levels, body weights and body-fat percentages.
To make sure the drug itself wasn't causing the vascular damage, the researchers also gave doxycycline to mice that were not
genetically engineered to make uncoupling protein-1 in the aorta. The drug did not increase the prevalence of atherosclerosis
in those mice.
When Semenkovich's team first engineered mice to produce uncoupling protein-1 in skeletal muscle, those mice ate a high-fat
diet but were as physically fit as mice on a low-fat diet. One interpretation of these results was that making mitochondria
less efficient in skeletal muscle cells may be beneficial.
Mitochondria produce energy in a process that also can cause damaging, highly reactive byproducts. The researchers reasoned
that with less energy, there would be less damage. But when the vessels made uncoupling protein-1 and energy levels
decreased, the result was more stress and inflammation in the blood vessel wall.
"The cells in the blood vessel wall apparently were trying to compensate for their less powerful mitochondria," Semenkovich
says. "It is possible that the decreased energy stores induced by the uncoupling protein caused cells to move more oxygen
through the system. But the increased flux of oxygen through the blood vessel wall caused oxidative damage, high blood
pressure and atherosclerosis." That may be what happens as people age, according to Semenkovich. He says it's likely that
oxidative damage accumulates in cells, and the mitochondria eventually become defective. As cells try to compensate, more
damage accumulates. There also is evidence that a similar process occurs in birds. In a series of experiments in the 1970s,
researchers found that when pigeons develop atherosclerosis -- and some do -- their blood vessels have inefficient
mitochondrial metabolism prior to developing blockages.
"If abnormal cellular metabolism can cause atherosclerosis, then perhaps modifying that metabolism can treat or prevent it,"
he says. "We're very interested in the potential for nutritionally modifying these processes with specific fats."
One area of interest involves essential fatty acids, which regulate body functions such as blood pressure and blood clotting.
The body doesn't produce them, so they must be acquired through the diet. Deficiency in essential fatty acids is thought to
contribute to atherosclerosis. Armed with the results of this study, Semenkovich believes a deficiency in essential fatty
acids may cause changes in the way metabolism occurs in the blood vessel wall.
"It would be interesting to figure out how to take essential fatty acids, get them into the vessel wall and see if you could
treat atherosclerosis that way," he says.
As the research continues, Semenkovich is studying various modifications to the mouse diets to see whether it's feasible to
deliver essential fatty acids to blood vessels.
Bernal-Mizrachi C, Gates AC, Weng S, Imamura T, Knutsen RH, DeSantis P, Coleman T, Townsend RR, Muglia LJ, Semenkovich, CF.
Vascular respiratory uncoupling increases blood pressure and atherosclerosis, Nature; vol. 435:7041, pp. 502-506, May 26,
2005.
This study was supported by grants from the National Institutes of Health, Clinical Nutrition Research Unit, Diabetes
Research and Training Center, an American Diabetes Association Mentor-Based Postdoctoral Fellowship, and by institutional
resources provided by Washington University and the Siteman Cancer Center to the Proteomics Center at Washington University.
Washington University School of Medicine's full-time and volunteer faculty physicians also are the medical staff of
Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and
patient care institutions in the nation, currently ranked third in the nation by U.S. News & World Report. Through its
affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.
Contact: Jim Dryden
jdrydenwustl.edu
314-286-0110
Washington University School of Medicine
medinfo.wustl.edu