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Margaret
I. Rand
Associate Professor
B.Sc., University of Toronto, 1977
Ph.D., University of Toronto, 1982
Rijksuniversiteit Limburg (Maastricht), 1983-1984
McMaster University (Hamilton), 1985 |
Hospital for Sick
Children, Room 7019D
416-813-7764
margaret.rand@sickkids.on.ca |
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Function and Signal Transduction
in Blood Platelets
Research Synopsis
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Blood platelets
are important in hemostasis and the initiation, development,
and clinical complications of atherosclerosis, the underlying
cause of coronary heart disease. In response to injury
of blood vessels, platelet masses (hemostatic plugs or
arterial thrombi) accumulate as a result of specific responses,
including adhesion, formation of the aggregatory eicosanoid
thromboxane A2 (TXA2), secretion of granule contents,
and aggregation, that are mediated by activation of signal
transduction pathways. We are studying ways in which pathways
of aggregation and signal transduction can be altered
with the goal of gaining a better understanding of the
biochemistry of platelets in normal and disease states.
Ethanol
We have been investigating whether the epidemiological
observations that moderate consumption of alcohol is associated
with a decreased risk of the thromboembolic complications
of coronary heart disease are due, at least in part, to
an inhibitory effect of ethanol on platelet functions.
We found that acute ethanol in vitro is an inhibitor of
specific pathways of platelet aggregation via inhibition
of the activation or activity of phospholipases C and
A2; these investigations are being continued to gain more
precise knowledge of the action of acute ethanol on signal
transduction in platelets. Our results indicate that inhibition
of phosphoinositide-linked signal transduction may be
responsible for the significant reduction of experimentally-induced
formation of arterial thrombi that we have observed in
rabbits given acute doses of ethanol. In addition to studies
of the effects of chronic alcohol on platelets (from alcoholics),
we are presently developing an animal model (rabbits)
in which we can study the effects of chronic, moderate
alcohol consumption on platelet function and signal transduction.
Cholesterol
Although it has been reported that hypercholesterolemia,
a risk factor for atherosclerosis, is associated with
enhanced platelet responses, we have found that different
types of hypercholesterolemia have very different effects
on platelet functions. In rabbits with diet-induced hypercholesterolemia
(increased very low density lipoprotein-cholesterol),
platelets become enriched in cholesterol and are hypersensitive
to aggregation induced by TXA2-dependent and independent
mechanisms. In contrast, in the genetically-determined
hypercholesterolemia (increased low density lipoprotein-cholesterol)
in Watanabe Heritable Hyperlipidemic (WHHL) rabbits, platelets
do not appear to be enriched in cholesterol, and are hyposensitive
to aggregation mediated via TXA2. Future studies will
involve investigations of the alteration in signal transduction
in platelets from rabbits with diet-induced or genetically-determined
hypercholesterolemia, of whether platelet hypersensitivity
can be induced in WHHL rabbits by the feeding of cholesterol,
and of the interaction between ethanol and cholesterol
(or other dietary lipids) on platelet responses.
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Selected Publications
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Acute administration
of ethanol to rabbits inhibits thrombus formation induced
by indwelling aortic catheters. Rand, M.L., Groves, H.M.,
Packham, M.A., Mustard, J.F., & Kinlough-Rathbone, R.L.
(1990) Lab. Invest., 63, 742-745.
Functions of platelets from rabbits with diet-induced
hypercholesterolemia or Watanabe (WHHL) rabbits with genetically-determined
hypercholesterolemia. Gross, P.L., Rand, M.L., Barrow,
D.V., & Packham, M.A. (1990) Blood 76 (Suppl 1), 457a.
Effects of alcohol withdrawal on responses of platelets
from alcoholics. A study using platelet-rich plasma from
blood anticoagulated with D-phenylalanyl-L-prolyl-L-arginyl
chloromethyl ketone (FPRCH2Cl). Rand, M.L., Neiman, J.,
Jakowec, D.M., & Packham, M.A. (1990) Thromb. Haemostas.
63, 178-182.
Thrombin-induced inositol trisphosphate production by
rabbit platelets is inhibited by ethanol. Rand, M.L.,
Vickers, J.D., Kinlough-Rathbone, R.L., Packham, M.A.,
& Mustard, J.F. (1988) Biochem. J. 251, 279-284.
Effects of ethanol on pathways of platelet aggregation
in vitro. Rand, M.L., Packham, M.A., Kinlough-Rathbone,
R.L., & Mustard, J.F. (1988) Thromb. Haemostas. 59, 383-387.
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