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Graffiti on a building's wall can be a nuisance, but the kind
sticking to proteins in the blood can be used as a new indicator
for cardiovascular disease.
"It is like chemical fingerprints," said CWRU chemist Robert
Salomon.
Research on the oxidation of low density lipoproteins (LDL),
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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