QUOTE:
Chemist unlocks mysteries of cholesterol, heart disease
Contact Susan Griffith, 216-368-1004 or s...@po.cwru.edu
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.
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. UNQUOTE.
Note the point made: "When macrophages get gummed up
with oxidized lipids..."
This cannot happen if you ate a diet rich in saturated fatty acids and
very low in unsaturated fatty acids (assuming you don't consume
cholesterol that is already oxidized). Cholesterol can be oxidized by
in vivo lipid peroxidation, and that cannot occur with saturated fatty
acids. In a sense, this is as simple as "2+2=4," yet our great
"experts" are advising the opposite !
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