Toxin-binding Protein Linked To Cardiovascular Health

Previously known for its role in recognizing industrial pollutants such as dioxins, the protein also responds to the most toxic forms of a cholesterol-carrying molecule in the blood, report researchers from the University of Wisconsin-Madison School of Medicine and Public Health. The new findings suggest that the dioxin-binding protein, named AHR, may act as a general protective system for the body, recognizing potentially dangerous substances and prompting steps to eliminate them.

According to the new study, published Jan. 23 in the Proceedings of the National Academy of Sciences, AHR in blood vessel linings detects a misfolded form of low-density lipoprotein, or LDL, in the blood. In a healthy cardiovascular system, LDL ferries essential cholesterol and other fats throughout the body. However, overabundance of LDL - due to a high-fat diet or genetic predisposition - or accumulation of the misshapen form can lead to cholesterol buildup in blood vessels and cause atherosclerosis, one of the leading causes of death in the United States. Because excess misfolded LDL is known to trigger the plaques that block arteries, a method to regulate or reduce levels could have profound therapeutic value, explains UW-Madison oncology professor Christopher Bradfield, senior author of the study.

The new work also describes a likely source of the misfolded LDL. Molecules carried in the blood, including LDL, can be exposed to high levels of physical stress as they are pumped and bumped through the blood vessels. This phenomenon, known as fluid shear stress by scientists, can actually change the shape and function of these molecules, says lead author and graduate student Brian McMillan. Using narrow tubing to simulate blood vessels, he found that fluid shear stress was enough to transform healthy human LDL into the potentially toxic form associated with atherosclerosis.

However, he says, this is not the whole story. "The conundrum is, we have fluid shear stress in all of our vessels. But if you took blood samples from healthy individuals, you wouldn't find much AHR-activating LDL," McMillan says, referring to the misshapen form.

Instead, he believes the much-maligned cholesterol carrier normally prompts its own purging from the bloodstream by activating key changes, such as AHR signaling, that ultimately eliminate the misfolded molecule.

Although ongoing surveillance may be sufficient to clean up normal levels of misfolded LDL, any imbalance in this system could spell trouble. McMillan and Bradfield found that mice lacking functional AHR had four times as much of the dangerous LDL activity in their blood as normal mice. Bradfield explains that this result may indicate that the AHR protects against cholesterol-induced damage, sensing the misshapen LDL and triggering steps to remove it before it causes problems in the body.

AHR acting as a molecular security guard is not a new idea - it was already well known for its role in protecting against damage from many common environmental contaminants, binding to them if they enter the body and prompting enzymes that break them down. However, high levels of AHR activity, such as those resulting from extremely potent environmental toxins such as dioxins, have been linked to human health problems including cancer, birth defects, immune suppression and cardiovascular disease.

Why the apparent discrepancy? Bradfield explains that even protective mechanisms can be damaging if overworked and moderation is key. "Only when you push the button too hard ý do you start to see negative effects," he says. "However, when the button isn't pressed at all we also see damaging effects to the body's organs."

Next, McMillan and Bradfield plan to study the health consequences of the AHR pathways in relation to LDL and cardiovascular disease by looking at effects of diet and genes. "Can the level of AHR signaling affect the progression of atherosclerosis in mice genetically or nutritionally predisposed to this disease?" asks McMillan.

Bradfield hopes their research will eventually lead to advances in treating cardiovascular disease. In biomedical research, he says, "It's common to first find the bad actor for a receptor system," such as environmental toxins and misfolded LDL, "then figure out how to use it therapeutically." Bradfield says, "There's no therapeutic application for the AHR now but there absolutely will be in 10 years."

This work was supported by grants from the National Institutes of Health.