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.