A molecule thought to contribute to the development of heart disease appears instead to help suppress it, according to School of Medicine researchers.
When researchers fed a high-fat diet to mice lacking the molecule beta3 integrin, they found the exact opposite of what they expected: The mice developed lung inflammation and clogged arteries and about two-thirds of them died within six weeks.
The results suggest that long-term suppression of this molecule may exacerbate the development of heart disease, rather than prevent it.
The study appears online in the Proceedings of the National Academy of Sciences.
“We were amazed that these animals died from a high-fat diet,” said study principal investigator Clay F. Semenkovich, M.D., professor of medicine and of cell biology and physiology and director of the Division of Endocrinology, Metabolism and Lipid Research. “This uncovers an interesting role for beta3 as a potential mediator of inflammation and may help guide new drug development strategies.”
Beta3 sits on the surface of cells and interacts with other molecules in the body to help regulate functions like blood clotting and inflammation. Because one of the proteins it interacts with is critical for blood platelets to form clots, drugs that block the action of beta3 often are used to treat people who are having a heart attack.
In the past few years, many experts have hypothesized that long-term use of beta3 inhibitors may prevent arteries from clogging and thereby prevent heart attacks, which is the most common cause of death in the United States.
Preventing heart disease is an exciting prospect, considering that thousands of people die every year from a sudden ruptured plaque without having experienced any previous symptoms. The problem is particularly prominent, according to Semenkovich, in the current climate of high-fat diets and rising rates of obesity.
To test the role of beta3 in the development of clogged arteries (a condition called atherosclerosis), the School of Medicine team developed a strain of mice that lacked beta3 and a protein called apolipoprotein E (apoE). Mice without apoE are known to develop atherosclerosis and often are used as a model to study the disease.
When the team fed mice a high-fat diet akin to that of the typical American, 62 percent of the mice lacking both beta3 and apoE died within six weeks, compared to just 4 percent of those lacking only apoE.
Autopsies of eight mice missing beta3 and apoE revealed that the cause of death was lung inflammation.
In addition, fat-fed mice lacking beta3 and apoE had significantly more fatty buildup, or plaques, in the arteries of the heart than their solely apoE-deficient counterparts.
For example, they had 3.3 times the amount of plaque buildup clogging the thoracic aorta (the artery that extends from the heart down into the diaphragm) and 5.6 times the amount of atherosclerosis in the abdominal aorta, the largest artery below the diaphragm.
Even when fed a normal diet, these animals had up to three times the amount of atherosclerosis as those lacking only apoE.
“These results suggest that a complex interaction between beta3 and high-fat diets may contribute to heart disease and other inflammatory diseases,” Semenkovich said.
Puzzled by this finding, the team conducted the same test in mice lacking a protein called low-density lipoprotein receptor (LDLR).
After 10 weeks on a high-fat diet, 48 percent of mice lacking both beta3 and LDLR had died, while none of the mice lacking only LDLR died.
In addition, high fat-fed animals lacking both beta3 and LDLR had up to four times the amount of clogged arteries as those lacking only LDLR.
The team found that mice lacking beta3 that died while on the high-fat diet had significantly higher amounts of three proteins (CD36, CD40L and CD40) in their tissues. These three proteins are known to be important contributors to inflammation in several diseases.
“Although beta3 is critical for platelet function and suppression of beta3 may contribute to heart disease in mice, the relationships among platelets, inflammation and heart disease are poorly understood,” Semenkovich said. “This study begins to explain the interaction, but people shouldn’t use this as a reason to stop taking anti-platelet drugs as part of a strategy to prevent heart disease.
Anti-platelet drugs are effective in the proper clinical context. Our findings are in mice, and we need to be cautious about extrapolating these results to people.”