Heparin modulates integrin-mediated cellular adhesion: specificity of interactions with alpha and beta integrin subunits.
Heparin is known to influence the growth, proliferation, and migration of vascular cells, but the precise mechanisms are unknown. We previously demonstrated that unfractionated heparin (UH) binds to the platelet integrin alpha(IIb)beta(3), and enhances ligand binding. To help define the specificity and site(s) of heparin-integrin interactions, we employed the erythroleukemic K562 cell line, transfected to express specific integrins (alpha(v)beta(3), alpha(v)beta(5), and alpha(IIb)beta(3)). By comparing K562 cells expressing a common alpha subunit (Kalpha(v)beta(3), Kalpha(v)beta(5)) with cells expressing a common beta subunit (Kalpha(v)beta(3), Kalpha(IIb)beta(3)), we observed that heparin differentially modulated integrin-mediated adhesion to vitronectin. UH at 0.5-7.5 microg/ml consistently enhanced the adhesion of beta(3) expressing cells (Kalpha(v)beta(3),Kalpha(IIb)beta(3)). In contrast, UH at 0.5-7.5 microg/ml inhibited Kalpha(v)beta(5) adhesion. Experiments using integrin-blocking antibodies, appropriate control ligands, and nontransfected native K562 cells revealed that heparin's actions were mediated by the specific integrins under study. Preincubation of heparin with Kalpha(v)beta(3) cells enhanced adhesion, while preincubation of heparin with the adhesive substrate (vitronectin) had minimal effect. There was a structural specificity to heparin's effect, in that a low molecular weight heparin and chondroitin sulfate showed significantly less enhancement of adhesion. These findings suggest that heparin's modulation of integrin-ligand interactions occurs through its action on the integrin. The inhibitory or stimulatory effects of heparin depend on the beta subunit type, and the potency is dictated by structural characteristics of the glycosaminoglycan.
Da Silva
Monica S
MS
Department of Surgery, SUNY Upstate Medical University and Veteran Affairs Medical Center, Syracuse, NY, USA.
Horton
Jason A
JA
Wijelath
Jacqui M
JM
Blystone
Lisa W
LW
Fish
Wallace R
WR
Wijelath
Errol
E
Strand
Kurt
K
Blystone
Scott D
SD
Sobel
Michael
M
D000906:Antibodies / Q000494:pharmacology; D000925:Anticoagulants / Q000494:pharmacology; D001773:Blood Cells / Q000187:drug effects* / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism; D002809:Chondroitin Sulfates / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006025:Glycosaminoglycans / Q000737:chemistry / Q000378:metabolism; D006493:Heparin / Q000494:pharmacology*; D006801:Humans; D039001:Integrin alpha Chains / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D039641:Integrin beta Chains / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D008970:Molecular Weight; D021122:Protein Subunits / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D019096:Vitronectin / Q000378:metabolism
D000906:Antibodies; D000925:Anticoagulants; D006025:Glycosaminoglycans; D039001:Integrin alpha Chains; D039641:Integrin beta Chains; D021122:Protein Subunits; D019096:Vitronectin; D006493:Heparin; D002809:Chondroitin Sulfates