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| | Interviews with Nutritional Experts: How Vitamin E Prevents Heart Disease | |
Interview with Dr. David Janero
as interviewed by Richard A. Passwater PhD
In recent columns, I have presented the evidence that vitamin E and other
antioxidant nutrients are protective against heart disease. People -- especially
scientists -- have trouble understanding this fact until they know "how"
vitamin E accomplishes this feat.
One scientist -- a cell biologist and biochemist -- has done much to establish
the necessary cellular evidence elucidating the protective mechanism. Dr.
David Janero is a member of the senior staff in the Cardiovascular- Atherosclerosis
Research Department of CIBA-GEIGY Corporation, Pharmaceuticals Division.
He conducted his Ph.D. work in cell biology at the Yale University School
of Medicine and was a National Institutes of Health Postdoctoral Fellow
in biological chemistry at the Johns Hopkins University School of Medicine.
Since 1983, he has held various research and development positions in the
pharmaceutical industry. Dr. Janero and his research team have contributed
to an increased understanding of the mechanisms of cardiovascular disease
and have helped define the potential of both novel therapeutics and natural
products (particularly vitamin E) to satisfy associated medical needs.
Their research findings are published in over 90 scientific reports and
have been presented at many professional meetings, most recently at the
Federation of American Societies for Experimental Biology conference "Vitamins
E and C and Free Radical Reactions." I have asked Dr. Janero to explain
how vitamin E protects against heart disease. I have set the stage in the
previous column with Dr. Lester Packer, who explained how vitamin E stops
free radicals including the lipid peroxidation process. Now Dr. Janero will
help me continue the story. We discuss many of the ways in which vitamin
E works to prevent heart disease, and then we look at the specific role
of how vitamin E prevents low-density lipoprotein from becoming oxidized.
This is the common ground that now has all cardiovascular researchers excited.
Passwater: You study heart disease from a different perspective
than "traditional" heart researchers -- pathologists, cardiologists,
and epidemiologists. You are trained as a cell biologist and biochemist,
yet clinical cardiologists are learning from your work.
What does your cellular and biochemical perspective bring to heart disease
research?
Janero: Modern cell biology uses concepts and technology from
many disciplines, including physical sciences such as chemistry and physics,
to help elucidate how the basic unit of life, the cell, functions in health
and disease. The critical importance of cell biology to medicine stems from
a principle elucidated over a century ago: all disease has a basis in abnormal
cell function. Biochemistry provides ways of probing and explaining cell
function in quantitative terms. Consequently, the combination of cell biology
and biochemistry is a powerful experimental avenue for me as a researcher
on the origins and mechanisms of cardiovascular disease. Cell biology and
biochemistry provide essential information to the physician who must understand
disease mechanisms in treating cardiac patients and optimize potential means
of prevention/therapy. The link between modern medicine and modern therapeutics
is the cell biology of disease.
Passwater: The timing seems good for new research approaches
such as your laboratory's. Many theories on the development of atherosclerosis
that once were thought to "hold water" are now considered full
of holes. Would you give us a brief overview of the current theory of "spontaneous
atherosclerosis?"
Janero: In the 1800's, anatomists recognized that
atherosclerosis is manifest as lipid-rich deposits in the walls of blood
vessels, particularly certain arteries (hence, the alternative name "arteriosclerosis").
Such fat deposits reduce the vessel opening, thereby limiting the nutritive
blood supply to whatever tissue or organ is downstream. Despite considerable
research, the details of how atherosclerotic vessel disease develops remain
elusive. Early thinking favored the concept that disruption or loss of the
thin layer of cells lining the artery (the endothelium) precipitated atherosclerosis.
Although rapid vessel blockage does occur after physical endothelial dosage,
this accelerated form of vessel disease is distinct from "spontaneous"
atherosclerosis.
Routine, spontaneous atherosclerosis is an injury response by the artery
wall which develops chronically (over decades in humans) in the presence
of extrinsic "risk factors" (e.g., high blood pressure, smoking,
diabetes, excesses of certain blood lipids) that increase the likelihood
of the first overt sign of atherosclerosis, the lipid deposit in the vessel
wall termed the "fatty streak" because it consists of frothy-looking,
lipid-laden "foam cells."
Although arteries in the body change structurally with time, this age-related
differentiation is not pathologic and does not itself lead to atherosclerosis.
Passwater: Tell us a little about the structure of arteries.
Janero: Arteries are a type of blood vessel which receive nutrient-rich
blood from the heart and conduct it to the major body organs. In humans,
relatively large artery diameters mean that about 20% of the total circulating
blood volume flows within these vessels. Generally, the artery wall contains
an endothelial lining, one cell-layer thick, in direct contact with the
circulating blood. Considerable connective tissue and smooth muscle are
below the endothelium to support the artery and at the same time give the
artery wall a fair degree of flexibility.
Passwater: Why did early researchers believe that cholesterol would
just "zap" from the blood into the artery wall?
Janero: The mechanism by which certain cells in the artery wall (particularly
so-called monocyte-macrophage cells) internalize circulating fat to form
lipid-rich foam cells has been detailed only within the last 20 years or
so. The research sought to explain a contradiction: lipid-laden foam cells
tend to develop when blood low-density lipoprotein (LDL) levels are high,
yet circulating LDL "fed" to isolated macrophages is not taken
up by these cells.
Research on the cell biology of this seeming anomaly demonstrated that unregulated
internalization of damaged or "modified" LDL particles through
specific "scavenger receptors" on the macrophage surface leads
to foam cell formation. The most pathologically relevant modification of
LDL seems to be oxidation (i.e., free radical-mediated peroxidation of LDL
polyunsaturated fatty acids). Therefore, oxidative lipoprotein damage can
be considered a driving force for early lesion (i.e., fatty streak) formation
[1].
Passwater: Conversion of smooth muscle cells of the artery wall into
proliferating cells also seems important to the progression of atherosclerosis.
What causes this conversion? Free radicals?
Janero: Smooth muscle proliferation is likely induced by small-molecule
"messengers" released from nonmuscle cells (such as endothelial
cells) in the artery wall. Growth factors within smooth muscle cells may
regulate their proliferative response to exogenous chemical signals. It
remains to be determined whether oxidants directly modulate the proliferative
response.
Passwater: Do atherosclerotic lipid deposits appear mostly in specific
arteries and/or at particular locations within arteries?
Janero: Atherosclerosis has a predisposition for critical arterial
beds comprised of medium-sized arteries, e.g., the coronary and carotid
arteries supplying heart muscle and brain, respectively, with nutritive
blood. Potentially important predisposing factors in arteries may be the
rather high oxygen tension of the blood flowing through them and the considerable
hydrostatic pressure generated. But there is significant variability both
along the length of the artery and around its circumference regarding the
pattern of lipid deposition within the arterial wall. This variation is
believed to reflect both blood-flow dynamics and the chronic, cumulative
nature of the lipid build-up itself.
Passwater: Why might vitamin E protect against atherosclerosis?
Janero: The idea that vitamin E may help prevent the initiation
and/or progression of spontaneous atherosclerosis is suggested by five main
lines of largely experimental evidence:
| Richard A. Passwater, Ph.D. has been a research biochemist since 1959. His first areas of research was in the development of pharmaceuticals and analytical chemistry. His laboratory research led to his discovery of......more |  |
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