Scientists Suggest that Fat Protein Helps Protect Against Blood Vessel Damage

06/06/07 A natural substance secreted by fat cells can protect blood vessels from the damaging effects of inflammation, one of the factors that contribute to heart disease. Researchers at Jefferson Medical College have shown for the first time in an animal model that the substance – a protein called adiponectin – helps prevent immune system white blood cells from binding to the inside of blood vessel walls. Harnessing adiponectin’s properties, the scientists suggest, may someday help protect against the blood vessel damage so prevalent in patients with obesity and diabetes.

Reporting June 1, 2007 in the Journal of Clinical Investigation, researchers led by Barry Goldstein, M.D., Ph.D., professor of medicine and director of the Division of Endocrinology, Diabetes and Metabolic Diseases and Rosario Scalia, M.D., Ph.D., associate professor of molecular physiology and biophysics, both of Jefferson Medical College of Thomas Jefferson University in Philadelphia, discovered that mice lacking adiponectin had an increase in so-called “adhesion” molecules and high levels of white blood cells sticking to the inside of blood vessel walls, which are signs of inflammation. When they gave the animals the “active” piece of the normal adiponectin molecule for 10 days, inflammation in the blood vessels was greatly reduced.

“This is translational work,” says Dr. Scalia. “We’ve used a mouse model to prove conceptually what we see in a test tube system in isolated cells is relevant to an intact physiological system. It’s a necessary step before going to humans. These results suggest that perhaps restoring this protein could be important to preventing atherosclerosis and vascular disease.”

They used a technique, intravital microscopy, which permits researchers to illuminate blood vessels using fluorescent signals, enabling them to “see” reductions in white cells on the vessel wall and subsequent lessening in inflammation.

The scientists also looked at the effects of adiponectin on inflammation in normal mice. They gave mice a substance, TNF-alpha, which caused the release of inflammatory substances called cytokines. Injecting the mice with the active adiponectin-fragment reversed the effects of the cytokines and the resulting inflammation.

Inflammation is common in cardiovascular disease. Adiponectin has been shown in cells in culture to block some “adhesion molecules” and receptors that are necessary for white blood cells to interact with the vessel wall, explains Dr. Scalia. “This is the first study to show in animals that this is one of the key mechanisms involved in this protein’s anti-inflammatory effect on the vascular system,” he notes. “That suggests thinking about either activating the receptors of the target of this protein or administering the fragment.”

Adiponectin is the most abundant protein found in the bloodstream that originates from fat tissue, and circulates as large complexes. Low levels of adiponectin are associated with obesity, diabetes and heart disease. The fragment, called the globular domain, can function as an active, anti-inflammatory part, notes Dr. Goldstein. “The findings demonstrate clearly that the fragment has the active portions,” he says. “Since the globular domain is relatively easy to produce, it could eventually lead to clinical trials taking advantage of its effects in the vasculature in inflammation.”

“What’s novel about the work is that it’s in animals, and involves a specialized technique in Dr. Scalia’s laboratory in which you can visualize the interaction between the white blood cell and blood vessel wall,” says Dr. Goldstein.

Studying normal mice, Dr. Goldstein notes, is an important aspect of the work. While using genetically altered mice is crucial, animals completely lacking adiponectin don’t exactly mimic the human condition. Most obese individuals, for example, at least have low levels of adiponectin. Part of the work demonstrated that adiponectin also protected against vascular inflammation in normal mice, a result that helps to relate the findings to humans with increased risk of vascular disease.

Next, Dr. Scalia says, they would like to better understand how adiponectin prevents the increase in white blood cell-blood vessel “anchoring” molecules in disease conditions.

The group is also testing the effects of adiponectin in conditions mimicking diabetes by exposing cells in the laboratory and blood vessels in animals to high glucose levels. “High glucose also causes dramatic inflammatory changes in the blood vessel lining,” Dr. Goldstein says. “We’re working to determine whether adiponectin can also reverse these changes. This process is occurring in every patient with high blood sugars and we are hoping that adiponectin can reverse the adverse effects of glucose and protect the vessel wall from damage.”