This Article Full Text Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wen, F.-Q. Articles by Valentino, L. A. Search for Related Content PubMed PubMed Citation Articles by Wen, F.-Q. Articles by Valentino, L. A. Pubmed/NCBI databases Substance via MeSH Related Collections Pathophysiology Cell biology/structural biology Platelets

(Arteriosclerosis, Thrombosis, and Vascular Biology. 1999;19:519-524.)
© 1999 American Heart Association, Inc.

Original Contributions

Atherosclerotic Aortic Gangliosides Enhance Integrin-Mediated Platelet Adhesion to Collagen

Fei-Qiu Wen; Adnan A. Jabbar; Dharmesh A. Patel; Tamara Kazarian; Leonard A. Valentino

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, G_M3 and G_D3, were tested. G_M3 increased adhesion to collagen (OD₅₇₀, 0.415±0.06) as did G_D3 (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

This article has been cited by other articles:

				D. K. Sharma, J. C. Brown, Z. Cheng, E. L. Holicky, D. L. Marks, and R. E. Pagano The Glycosphingolipid, Lactosylceramide, Regulates {beta}1-Integrin Clustering and Endocytosis Cancer Res., September 15, 2005; 65(18): 8233 - 8241. [Abstract] [Full Text] [PDF]

				Z. Wang, T. M. Leisner, and L. V. Parise Platelet {alpha}2{beta}1 integrin activation: contribution of ligand internalization and the {alpha}2-cytoplasmic domain Blood, August 15, 2003; 102(4): 1307 - 1315. [Abstract] [Full Text] [PDF]

				B. Garner, D. A. Priestman, R. Stocker, D. J. Harvey, T. D. Butters, and F. M. Platt Increased glycosphingolipid levels in serum and aortae of apolipoprotein E gene knockout mice J. Lipid Res., February 1, 2002; 43(2): 205 - 214. [Abstract] [Full Text] [PDF]

				I. Gouni-Berthold, C. Seul, Y. Ko, J. Hescheler, and A. Sachinidis Gangliosides GM1 and GM2 Induce Vascular Smooth Muscle Cell Proliferation via Extracellular Signal-Regulated Kinase 1/2 Pathway Hypertension, November 1, 2001; 38(5): 1030 - 1037. [Abstract] [Full Text] [PDF]

				M. J. Hewish, Y. Takada, and B. S. Coulson Integrins alpha 2beta 1 and alpha 4beta 1 Can Mediate SA11 Rotavirus Attachment and Entry into Cells J. Virol., January 1, 2000; 74(1): 228 - 236. [Abstract] [Full Text]