Scripps Scientists Link Ozone to Atherosclerosis
Detection of Toxic "Atheronal" Molecules May Lead to New
Diagnostics
By Jason Socrates
Bardi
A team of investigators led by The Scripps Research Institute
(TSRI) President Richard A. Lerner, and TSRI Associate Professor
Paul Wentworth, Jr., are reporting evidence for the production
of ozone in fatty atherosclerotic plaques taken from diseased
arteries.
Lerner, who is is Lita Annenberg Hazen Professor of Immunochemistry
holds the Cecil H. and Ida M. Green Chair in Chemistry at
TSRI, and is a member of TSRI's Skaggs Institute for Chemical
Biology, Wentworth, and their colleagues have been looking
at the production of ozone molecules within the human body
for the last year and a half—ever since they made the
completely unexpected discovery that human antibodies generate
a product with the chemical signature of ozone. Ozone is a
highly reactive molecule that has never before been considered
part of biology.
So if antibodies produce ozone in the human body, the TSRI
scientists asked, what is the ozone doing there? Their report,
out in this week's issue of the journal Science, details
what they found.
In their report, Lerner, Wentworth, and their colleagues
describe how ozone can trigger pathological changes in other
molecules in the body, like cholesterol, which ozone breaks
down to produce toxic compounds. The scientists describe two
such compounds, which they call the "atheronals." These atheronals
were found in atherosclerotic plaques that were surgically
removed from patients with atherosclerosis.
The scientists suggest these newly identified products are
critical to the pathogenesis of atherosclerosis because they
are toxic to white blood cells, smooth muscle cells, and cells
from the arterial walls—all the major types of cells
in and around atherosclerotic plaques. Furthermore, they suggest
that atheronals and similar products of ozonolysis may contribute
to a number of other diseases, such as lupus, multiple sclerosis,
and rheumatoid arthritis.
"Ozone is damaging, and it is really a problem that we are
going to have to think about in the next few years," says
Wentworth. "There may be a whole slew of molecules that ozone
generates that we have never thought about before."
Finally, Lerner, Wentworth, and their colleagues detail
how one of the atheronals was found in the blood of patients
who have late-stage atherosclerosis, but not in healthy individuals.
This suggests that the presence of atheronals may be a good
indicator of late-stage arterial inflammation—perhaps
the basis for a diagnostic test for atherosclerosis.
Currently, physicians use other risk factors to identify
a patient's risk: elevated cholesterol, hypertension, diabetes,
smoking, obesity and a family history of vascular disease
at an age less than 55. These indicators are not always reliable,
and there is a substantial fraction of patients who develop
atherosclerosis without displaying these risk factors.
Sensitive diagnostic markers that would allow early identification
of patients at risk of life-threatening atherosclerosis would
be a boon to preventative medicine.
Atherosclerosis and Ozone Atherosclerosis is a common vascular
disease that increases the risk of heart attacks and strokes.
In fact, heart disease is the most common cause of death in
the United States. The Centers for Disease Control and Prevention
statistics for 2000 list 878,471 deaths from heart disease
and stroke, followed by 553,091 for cancer.
The name of the disease comes from the Greek athero (which
means gruel or paste) and sclerosis (which means hardness).
And, as the name implies, it is a disease that is characterized
by a hardening of the arteries over time due to the buildup
of hard plaques—fibrous tissue, calcium, fat, cholesterol,
proteins, cells, and other materials—on the inner "endothelial"
walls of an artery. These plaques feel something like cartilage
to the touch, which explains why atherosclerosis is commonly
called hardening of the arteries.
Over the last few years, evidence has been accumulating
that the process of atherosclerosis has a significant inflammatory
component. Given this evidence, Lerner, Wentworth and their
colleagues thought they would look at tissue involved in the
disease for evidence of ozone.
Ozone is a particularly reactive form of oxygen that exists
naturally as a trace gas in the atmosphere, constituting on
average fewer than one part per million air molecules. The
gas plays a crucial role in protecting life on earth from
damaging solar radiation by concentrating in the upper reaches
of Earth's stratosphere—about 25 kilometers above the
surface—and absorbing ultraviolet radiation. Ozone is
also a familiar component of air in industrial and urban settings
where the highly reactive gas is a hazardous component of
smog in the summer months.
Lerner and Wentworth realized that atherosclerotic plaques
have all the ingredients needed to make ozone. They contain
white blood cells, which have the ability to generate the
singlet oxygen that the antibodies need to produce ozone—and
plenty of antibodies passing by in the blood stream.
Ozone Present in Atherosclerotic Plaques Last year, Lerner
and Wentworth approached Giacomo DeLaria, M.D., who is a vascular
surgeon at nearby Scripps Clinic, and asked if they could
obtain samples of carotid atherosclerotic plaques. DeLaria
provided a sample of plaque material from a patient who recently
underwent an endarterectomy, generously enabling Wentworth,
Lerner, and their colleagues to perform their studies. Endarterectomies
are common surgical procedures to remove plaques from the
inner walls of atherosclerotic arteries.
"These are specimens we normally just inspect and throw
away," says DeLaria, who is a coauthor of the study. "Within
themselves, they have no diagnostic value, and they don't
change what we do after the procedure."
Wentworth and Lerner tested this sample, and the results
proved promising. They found some abnormalities that could
be associated with the presence of ozone in these plaques.
But they wanted to be sure. So DeLaria and his fellow vascular
surgeon Ralph Dilley, M.D., provided several more samples.
When Lerner, Wentworth, and their colleagues studied the
atherosclerotic plaque samples, they found the evidence they
were looking for. The atheronals—signature products that
were produced when the highly reactive ozone mixed with cholesterol—were
evident in the plaques. This suggests that ozone production
occurred as these plaques were being formed.
The article, "Evidence for Ozone Formation in Human Atherosclerotic
Arteries" is authored by Paul Wentworth Jr., Jorge Nieva,
Cindy Takeuchi, Roger Galve, Anita D. Wentworth, Ralph B.
Dilley, Giacomo A. DeLaria, Alan Saven, Bernard M. Babior,
Kim D. Janda, Albert Eschenmoser, and Richard A. Lerner. The
article will be published in the November 7, 2003 issue of
the journal Science, and it will be available online to Science
subscribers this week at: http://www.sciencemag.org.
The research was funded by the National Institutes of Health
(NIH) research and training grants; by La Secretaria de Estado
de Educacion y Universidades and El Fondo Social Europeo;
and by The Skaggs Institute for Research.
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These lipid-laden macrophages provide
evidence of ozone generation in human atherosclerotic arteries.
Image by Cindy Takeuchi and Bob Turner.
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