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Emerging Views of Heparan Sulfate Glycosaminoglycan Structure

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Emerging Views of Heparan Sulfate Glycosaminoglycan Structure chain contains a b-D-glucosamine linked to an uronic acid, which can be one of two C5 epimers, either a-L-iduronic or b-D-glucuronic acid. Other than the C5 Emerging Views of Heparan Sulfate position of the uronic acid, HLGAGs Glycosaminoglycan Structure/Activity vary in their chain length, that is, the number of disaccharide repeat units, and Relationships Modulating Dynamic degree of sulfation and acetylation of each disaccharide unit. O-sulfation of the Biological Functions disaccharide repeat can occur at the 2-O Zachary Shriver, Dongfang Liu, and Ram Sasisekharan* position of the uronic acid and the 6-O and 3-O positions of the glucosamine. Thus, for a given disaccharide unit within an HSGAG structure, each site is Heparan sulfate glycosaminoglycans (HSGAGs) are an important subset either sulfated or unsubstituted, creat- of complex polysaccharides that represent the third major class of biopoly- ing eight possible combinations. In ad- mer, along with polynucleic acids and polypeptides. However, the impor- dition, as mentioned above, there are two possibilities for the uronic acid com- tance of HSGAGs in biological processes is underappreciated because of a ponent of each disaccharide unit, that lack of effective molecular tools to correlate specific structures with func- is, either iduronic acid or glucuronic tions. Only recently have significant strides been made in understanding acid, giving rise to a total of 16 different the steps of HSGAG biosynthesis that lead to the formation of unique possible disaccharide combinations. Fi- nally, the N-position of the glucosamine structures of functional importance. Such advances now create possibili- can be sulfated, acetylated, or unsubsti- ties for intervening in numerous clinical situations, creating much-needed tuted (three possible states). Taking this novel therapies for a variety of pathophysiological conditions including final factor into account results in 48 atherosclerosis, thromboembolic disorders, and unstable angina. (Trends possible disaccharide building blocks. Cardiovasc Med 2002;12:71–77). © 2002, Elsevier Science Inc. Thus, HSGAGs have the potential to carry more information than any other biopolymer, including either DNA (made up of four bases) or proteins (made up Heparan sulfate-like glycosaminoglycans to be important regulators of biological of 20 amino acids). Consider, for in- (HSGAGs) are complex acidic polysac- processes ranging from embryogenesis stance, a simple polymer of each kind charides present both within the extra- (Perrimon and Bernfield 2000) to hemo- made of six units. For DNA, there are 46 cellular matrix (ECM) that surrounds stasis (Rosenberg et al. 1997) as well as or 4096 possible sequences for this hex- cells and at the cell surface as protein– in the pathophysiology of disease states, amer. In contrast, for a hexapeptide, carbohydrate conjugates (termed proteo- such as atherosclerosis and thromboem- there are many more possibilities, 206 or glycans) (Figure 1). HSGAG proteogly- bolic disorders (Kolset and Salmivirta 64 million possible permutations. How- cans are found at the surface of virtually 1999). This review focuses on recent sci- ever, for HSGAGs, a polymer made of every cell type, where they act as impor- entific advances that have furthered our six disaccharide units could have a total tant biological mediators of various cell- understanding of how HSGAG structure of over 12 billion possible sequences, a related events such as proliferation, impinges on function. Specific emphasis staggering degree of variation, over 100 morphogenesis, adhesion, migration, and will be placed upon how these advances times as much as for polypetides and cell death (apoptosis) (Sasisekharan have increased our appreciation of the two million times that of DNA! and Venkataraman 2000; Tumova et al. importance of complex polysaccharides 2000). Given their role in fundamental in vascular biology, and how this under- • HSGAGs in Cardiovascular cellular events, HSGAGs have been found standing offers new potential for the de- Hemostasis velopment of novel classes of therapeutics. That HSGAGs can regulate such a va- Given the information density of HSGAGs, Zachary Shriver, Dongfang Liu, and Ram riety of biological processes is a function each HSGAG chain contains multiple Sasisekharan are from the Division of Bioengineering and Environmental Health of the chemical diversity inherent in the sequences that specifically regulate mul- and the Center for Biomedical Engineering, HSGAG polymer. A disaccharide repeat tiple components of the cardiovascular Massachusetts Institute of Technology, Cam- unit characterizes all HSGAGs; however, system (Figure 2a). In some cases, it has bridge, MA. HSGAGs from various sources differ been shown that certain HSGAG struc- * Address correspondence to: Dr. R. Sasise- both in terms of their length (that is, the tures provide protective effects against kharan, MIT, 77 Massachusetts Avenue, number of disaccharide repeat units) and disease processes such as atherosclero- Building 16-561, Cambridge, MA 02139, sis and unstable angina (Kanabrocki et USA. Tel.: (11) 617-258-9494; fax: (11) 617- differential chemical modifications within 258-9409; e-mail: [email protected]. the HSGAG chain (Figure 1) (Salmivirta al. 1992). For instance, HSGAGs lining © 2002, Elsevier Science Inc. All rights et al. 1996; Turnbull et al. 2001). the luminal surface of endothelial cells reserved. 1050-1738/02/$-see front matter Each disaccharide unit of an HSGAG effectively provide electronegativity, and TCM Vol. 12, No. 2, 2002 71 the atherogenic process. The pharmaco- logical administration of highly sulfated HSGAGs restores the electronegativity of the damaged endothelium lining, thereby limiting further damage and preventing thrombosis. In addition, cell surface HSGAGs, through interactions with lipoprotein lipase and apolipopro- teins B and E, are involved in the metab- olism of lipoproteins including HDL by regulating their uptake and metabolism (Figure 2a) (Kolset and Salmivirta 1999, Rosenberg et al. 1997). In this manner, HSGAGs mediate the “lipid clearing effect” of plasma. Finally, cell surface HSGAGs, depending on structure and concentration, can either inhibit or pro- mote growth factor signaling, thus regu- lating SMC proliferation during vascular stenosis and atherosclerosis. Importantly, many of these biological observations have been successfully translated to the clinic; specific examples will be illustrated below. The protective effects of highly sulfated HSGAGs have been extensively demon- strated in coronary diseases such as myo- cardial infarction and unstable angina. Thus, HSGAG structures impinge on vascular biology in multiple ways. To differentiate roles for specific HSGAG sequences requires the application of newly developed technologies for the isolation and characterization of biolog- ically important HSGAG sequences. Be- low, we focus on two specific examples where such studies have offered a clear understanding of how specific HSGAG structures impinge on function, result- ing in significant advances both scientif- ically and clinically. • HSGAGs in Coagulation Of the many functions regulated by HS- GAGs, one of the best studied is their Figure 1. HSGAGs at the cell surface modulate signaling pathways. HSGAGs exist at the cell role in the maintenance of hemostasis, surface as protein conjugates called proteoglycans. Due to the highly hydrophilic nature of the or regulation of blood volume and com- HSGAG chains, proteoglycans have a “Christmas tree”-like appearance. In addition, zooming position. In vivo, under normal, non- in on the HSGAG proteoglycans structure, the biosynthesis of HSGAGs leads to regions of ag- pathologic conditions, HSGAGs at the gregate chemical character in the polysaccharide chain. The darkened squares indicate under- surface of endothelial cells actively mod- sulfated regions of the polysaccharide chain, whereas the empty circles indicate regions of high sulfation. Zooming in further, all HSGAGs are comprised of a disaccharide unit of uronic ulate the activity of the proteases involved acid (either iduronic acid [I] or glucuronic acid [G]) attached to a hexosamine [H]. Each disac- in the coagulation cascade, including tis- charide unit can be differentially sulfated at the 2-O position of the uronic acid [2S] and/or the sue factor, factor Xa, and factor IIa 6-O [6S], 3-O [3S], and N [NS] positions of the hexosamine. The shorthand nomenclature is (thrombin), among others (Figure 2b) shown in brackets. Thus, the disaccharide structure in the figure is abbreviated GHNS,3S,6S rep- (Rosenberg 2001). As might be expected → resenting glucuronic acid 1 4 N-sulfoglucosamine 2,6-disulfate. from such an information dense mole- cule, HSGAGs impinge on almost every a hydration sphere to the vascular wall (Figure 2a). The disruption of this lining step of the coagulation cascade, mean- that is important for the normal tone by direct injury to the blood vessels is ing that these complex polysaccharides and fluidity of the circulating media one of the primary initiating factors of play multifaceted roles in maintaining 72 TCM Vol. 12, No. 2, 2002 the interaction of HSGAGs with anti- thrombin III (ATIII) (Figure 3) (Jin et al. 1997). The entire coagulation process is under the control of a group of glyco- protein serine protease inhibitors (also known as serpins), the most important of which is ATIII. Many of the coagula- tion proteases, most notably factor Xa and IIa, are inhibited by ATIII, which forms an equimolar inhibitory
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