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CHEMIST UNLOCKS MYSTERIES OF CHOLESTEROL, HEART DISEASE
"It is like chemical fingerprints," said CWRU chemist Robert Salomon. Research on the oxidation of low density lipoproteins, the so called "bad cholesterol," led to the discovery by Salomon, professor of chemistry, of isolevuglandins and other toxic oxidized lipids that form this graffiti on proteins. Pure samples of isolevuglandins and other oxidized lipids prepared synthetically in Salomon's research provide doctors at the Cleveland Clinic (John Crabb, Stanley Hazen, Henry Hoff, Joe Hollyfield and Eugene Podrez), with valuable tools and information for studies of heart disease, macular degenerative disorders and other diseases brought on by oxidative damage of lipids. He credits the research link between CWRU and the Clinic as making the connection between the chemistry lab and biological processes. The clinical groups suspected the involvement of oxidized lipids in pathological processes they were studying, he said, but the amounts of these lipids in biological specimens were so minute that progress was stymied until methods were developed for making virtually unlimited amounts of pure oxidized lipids in the chemical laboratory. The National Institutes of Health recognized Salomon's ground-breaking research with a new four-year, $1.4 million research grant for the study, "Preprostaglandin Endoperoxides." The grant continues 23 years of NIH support and expands upon research that has resulted in patents on detecting a variety of these "fingerprints" of lipid oxidation that can be used to read the "graffiti" on oxidatively damaged proteins in the blood. Through the development of antibodies that recognize the modified proteins, the researchers can measure the accumulation of them in human blood that may occur over days, weeks or even months. The quantity of the modified proteins correlates with cardiovascular disease, Salomon said. While many people have high levels of LDL, only a small fraction of them will develop heart disease. Salomon found that the "graffiti" resulting from oxidized lipids sticking to proteins is a better indicator of cardiovascular disease than the classical risk factors, high LDL or total cholesterol levels in the blood. Salomon also found that some people have an allergic reaction to the "graffiti" because their immune system responds to the altered proteins as if they were alien invaders. Preprostaglandin endoperoxides are unstable intermediates, produced throughout the body, from which hormone-like oxidized lipids are formed to promote blood clotting or thinning, depending upon the needs of the organism. Other endoperoxide-derived oxidized lipids produce pain and inflammation. The medicinal actions of aspirin and other nonsteroidal antiinflammatory drugs such as Celebrex, result from their ability to block the enzyme responsible for generating the endoperoxides. "We stumbled onto a non enzymatic process that transforms endoperoxides into toxic oxidized lipids, levuglandins, that stick to proteins and DNA," Salomon said. Similar endoperoxides are produced by nonenzymatic oxidation of lipids caused by free radicals. Salomon realized that when these endoperoxides are transformed into isolevuglandins they become "very reactive materials that act like a magnet that sticks to everything, including the protein in LDL particles." Macrophage cells, described as the garbage trucks of the blood, try to carry away oxidatively damaged LDL. When macrophages get gummed up with oxidized lipids, they "become bloated with partially digested lipoprotein and globules of cholesterol" and form "foam cells," Salomon said. Eventually foam cells develop into the atherosclerotic plaque found in cardiovascular disease. "Macrophages are supposed to clean up oxidatively damaged LDL but are covered with these toxic oxidized lipids that bring the whole process to a grinding halt," Salomon said. Isolevuglandins "spoil" the protein, according to Salomon, who added that antioxidants, like vitamin E, help protect the body against this bad chemistry. When the antioxidants fail, the damage from free radical oxidation occurs. Over the past decade, Salomon's research has expanded to other diseases such as macular degenerative diseases that result in blindness and involve "brain lipids" that contain an omega-3 fatty acid that is abundant in fish oil. Brain lipids are very rare in the body, but are found in nerve cells and in the photoreceptor rod cells of the eye. Salomon and Clinic researchers suspected that the energy from light on the receptors might promote oxidation and damage. Through mass spectroscopy studies, they have begun to see protein modifications that are similar to those in heart disease. Salomon's discoveries started with pure chemistry. "It became apparent that this chemistry was significant to human health," he said. "For years, I was in the mind frame that anything biological was magical, and that the chemistry that occurs in test tubes had little relevance to the chemistry that occurs in biological processes. "Slowly over the past decade, I have begun to realize that chemistry is part of the problem and part of the solution. Biology must adapt to the chemistry inherent in the molecules we're made of," he added.
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