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Professors investigate natural heart disease defense molecule

University researchers may shed light onto the body's natural defenses against inflammation of arteries, which ultimately can lead to heart attacks and strokes, in a study published last month in Science.

University Biomedical Engineering, Molecular Physiology and Biological Physics professor Dr. Klaus Ley and Dr. Yuqing Huo, began investigating epoxyeicosatrienoic acid -- or EET -- during the summer of 1996.

They collaborated with colleagues at Brigham & Women's Hospital and Harvard Medical School.

EET is a short-lived product of metabolism that can prevent inflammation in heart arteries. Inflammation refers to a body's response to tissue damage and usually is characterized by pain, redness and swelling.

"EET blocks one of the most important inflammatory transcription factors," Ley said.

Transcription factors are proteins effective in the initiation, stimulation or termination of genetic processes. They bind to promoters, turning a gene on and off. A promoter is a piece of DNA at the beginning of a gene that controls its expression.

EET inhibits the inflammatory transcription factor NFkB that would normally turn on the promoter. Increased levels of EET lead to less inflammatory cell adhesion to vessel walls. Without EET present, higher levels of white blood cells move into the vessel walls.

The enzyme that makes EET was discovered in the cells that coat the interior of blood vessels

EET previously was known to open blood vessels by relaxing smooth muscle cells in vessel walls. The study indicates that these molecules also have vascular anti-inflammatory properties.

"Before this research, EETs have been known for several years for their vasodilatory and other properties, our current study found that besides other properties, they can significantly inhibit expression of vascular cell adhesion molecules," Huo said.

Scientists intravenously infused the EET compound into two groups of mice that had developed atherosclerosis -- the progressive hardening and narrowing of the arteries over time.

The Department of Biomedical Engineering developed a mouse model suitable for investigating inflammatory cell adhesion in atherosclerosis. Models are used in research to mimic disease progressions.

The mice lacked apolipo-protein-E, a component of low-density lipoprotein, LDL. This altered their lipid/fat metabolism, making them more susceptible to atherosclerosis. These mice were similar to people with high "bad" cholesterol levels.

The scientists isolated a carotid artery in the mice to study the role of inflammatory adhesion molecules.

These molecules are expressed on the surfaces of cells that line blood vessels. The molecules bind leukocytes or white blood cells, which leads to inflammation.

Researchers observed the migration of inflammatory cells into atherosclerotic lesions using intravital microscopes. These tools were modified for use with living tissues. The microscopes can illuminate tissue with fluorescence and have special objective lenses that work underwater.

They then analyzed the migration rates of fluorescent-dyed cells using video recordings and a digital processing system.

Ley explained that the video recording allowed researchers to observe three stages of vascular activity. In the first stage, cells float though the artery, indicating normal blood flow. In the second stage, cells "roll" through the artery, showing the initial steps of inflammation. In the third and final stage cells stuck onto the atherosclerosis lesions.

"The next step is to find out which of these adhesion molecules are critical for atherosclerosis lesions," Ley said. "Then we will have to go back to patients and see if there is any correlation between mutations in the genes for the molecules and disease."

Ley is continuing research into various "bad" adhesion molecules that result in atherosclerotic plaque build up and how EET stops the adhesion molecules from being expressed. Future research into the role of EET involves manipulating the enzyme that synthesizes EET or changing the EET receptor.

EET itself does not have a future as a drug because it is too short lived, Ley explained. There is, however, the possibility of developing analogs -- stable molecules that have similar biological effects -- of the compound.

"Every piece of understanding that we got about how atherosclerosis works is likely to benefit patients," Ley said.