© 1999 American Heart Association, Inc.
Original Contributions |
Atherosclerotic Aortic Gangliosides Enhance Integrin-Mediated Platelet Adhesion to Collagen
From the Department of Pediatrics, Rush Medical College and Rush Children's Hospital, Chicago, Ill.
Correspondence to Leonard A. Valentino, MD, Rush Children's Hospital, 1653 W Congress Parkway, Chicago, IL 60612-3833. E-mail lvalentino{at}rush.edu
Abstract—Gangliosides, sialic
acid–containing glycosphingolipids, accumulate in atherosclerotic
vessels. Their role in the pathogenesis of
atherosclerosis is unknown. Gangliosides isolated from
tumor cells promote collagen-stimulated platelet aggregation and
ATP secretion and enhance platelet adhesion to
immobilized collagen. These activities are all mediated by
ganglioside effects on the platelet integrin collagen receptor
2ß1. Therefore, we hypothesized that
gangliosides isolated from atherosclerotic plaques would enhance
platelet adhesion to immobilized collagen, a major
component of the subendothelial matrix of blood
vessels. Furthermore, we questioned whether this effect of
atherosclerotic gangliosides might play a role in the pathogenesis of
atherosclerosis. To test this hypothesis, we isolated
the gangliosides from postmortem aortas of patients with extensive
atherosclerotic disease and examined their effects on platelet
adhesion. Samples of aortic tissue taken from areas involved with
atherosclerotic plaque demonstrated accumulation of gangliosides
(64.9±6.5 nmol/g wet weight) compared with gangliosides isolated from
control normal aortic tissue taken from children who died of noncardiac
causes (NAGs; 21.1±6.4 nmol/g wet weight). Interestingly, samples of
tissue taken from diseased aortas but from areas not involved with
gross plaque formation also demonstrated ganglioside accumulation
(47.6±12.8 nmol/g wet weight). Next, the activity of each of these
gangliosides on platelet adhesion to immobilized type I
collagen was studied. Atherosclerotic aortic gangliosides (AAGs) as
well as those isolated from grossly unaffected areas of the same aorta
(UAGs) both increased platelet adhesion compared with control NAGs
(OD570, 0.37±0.11 and 0.29±0.14 versus 0.16±0.07,
respectively; P<0.01 and P<0.05,
respectively). These OD570 values corresponded to
9x105, 8x104, and 6x103
platelets per well after preincubation with 5 µmol/L AAG,
UAG, and NAG, respectively. Increased adhesion was observed after
preincubation with as little as 0.5 µmol/L AAG, and maximal
adhesion was seen at 2.5 µmol/L, with a plateau extending to the
highest concentration tested, 10 µmol/L. The effect of AAGs on
platelet adhesion to collagen was abrogated by incubation of
treated platelets with F-17 anti-2 monoclonal
antibody (OD570, 0.13±0.02). Finally, the effects of the
major individual gangliosides isolated from atherosclerotic tissues,
GM3 and GD3, were tested. GM3
increased adhesion to collagen (OD570, 0.415±0.06)
as did GD3 (0.31±0.08). Similar to that of AAGs, the
effect of both molecules was blocked by F-17 (0.09±0.04 and
0.13±0.06, respectively). These experiments demonstrate that
accumulated atherosclerotic gangliosides promote platelet adhesion
to collagen, the major component of the subendothelial
matrix. Furthermore, this activity is mediated by an effect of the
gangliosides on the collagen-binding integrin
2ß1. This activity may provide a mechanism
for the development of platelet thrombi at sites where
atherosclerotic gangliosides accumulate and help to explain the role of
platelets in the process of atherosclerotic disease
progression.
Key Words: atherosclerosis • gangliosides • platelets • integrins
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