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Cardiovascular Research 2007 76(1):19-28; doi:10.1016/j.cardiores.2007.05.014
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Copyright © 2007, European Society of Cardiology

Glycosaminoglycan synthesis and structure as targets for the prevention of calcific aortic valve disease

K.J. Grande-Allena, N. Osmanb,c, M.L. Ballingerb, H. Dadlanib, S. Marascod and P.J. Littleb,c,*

aDepartment of Bioengineering, Rice University, Houston, TX USA 77005
bCell Biology of Diabetes Laboratory, Baker Heart Research Institute, Melbourne, Victoria, 3004, Australia
cDepartments of Medicine and Immunology, Central and Eastern Clinical School, Alfred Hospital, Monash University, Melbourne, 3004, Victoria, Australia
dDepartment of Cardiothoracic Surgery, Alfred Hospital, Melbourne, Victoria 3004, Australia

*Corresponding author. Cell Biology of Diabetes Laboratory, Baker Heart Research Institute, St. Kilda Rd Central, PO Box 6492, Melbourne Victoria 8008, Australia. Tel.: +61 3 8532 1203; fax: +61 3 8532 1100. peter.little{at}baker.edu.au

Received 14 February 2007; revised 7 May 2007; accepted 10 May 2007


   Abstract
Top
 Abstract
1. Introduction
 2. Current understanding of...
 3. Galactosaminoglycan fine...
 4. Regulation of HA...
 5. Pharmacological and...
 6. Conclusions
 References
 
Calcific aortic valve disease is frequently driven by ageing and the obesity-associated metabolic syndrome, and the increasing impact of these factors indicates that valve disease will become a cardiovascular disease of considerable significance. This disease is now thought to be an active cell-based disease process, which may therefore be amenable to therapeutic intervention. Some similarities are apparent with atherosclerosis. The accumulation of lipid, possibly by retention by proteoglycans and the attraction of inflammatory cells by hyaluronan, may be common to the early stages of both pathologies. The synthesis and structure of glycosaminoglycans, proteoglycans, and hyaluronan are exquisitely regulated, and the signalling pathways controlling these processes may provide tissue-specific opportunities for concomitant prevention of atherosclerosis and calcific aortic valve disease.

KEYWORDS Calcific aortic valve disease; Proteoglycans; Hyaluronan; Lipid retention; Inflammation


   1. Introduction
Top
 Abstract
 1. Introduction
2. Current understanding of...
 3. Galactosaminoglycan fine...
 4. Regulation of HA...
 5. Pharmacological and...
 6. Conclusions
 References
 
Aortic valve sclerosis and stenosis was originally considered to be the result of the natural degenerative ageing of inert matrix-based tissue, offering little opportunity for prevention or therapy [1]. More recently, the active and cell-based nature of the disease process has been recognized and thus the potential for intervention has arisen [2,3]. The natural history of calcific aortic valve disease (CAVD) begins with a long slow asymptomatic phase, in which the thickened leaflets do not obstruct ventricular outflow, followed by a calcific and stenotic stage when ventricular outflow is impeded, precipitating shortening of breath and left ventricular hypertrophy [4]. The prevalence of CAVD has been rising, at up to 5% in elderly patients, and represents the second most common indication for cardiac surgery. The frequent association of ageing [5] and the obesity-associated metabolic syndrome [6] with CAVD suggests that this condition is becoming a cardiovascular disease of major importance.

There is little prospective data on the rate or incidence of progression of aortic valve sclerosis to calcific aortic valve stenosis. However, retrospective reviews of large databases have shown that the incidence is appreciable. In a study of 400 patients, Faggiano et al. [7] documented progression to some degree of aortic stenosis in 32.75% of patients over 5 years. In a larger study of >2000 patients, the incidence of progression to aortic stenosis was 16% over an eight year follow up [8].

The only effective treatment is surgical replacement of the stenotic valve with a mechanical, bioprosthetic or biological valve [9]. However, this involves open heart surgery with its attendant risks. Also, structural deterioration of bioprosthetic valves is inevitable over time and mechanical valves require anti-coagulation therapy [9]. There is no current approved or recognized therapeutic treatment for CAVD.

Some pathological characteristics of CAVD resemble the development of atherosclerosis, but there are also several distinctions. Although both appear to start with lipid entrapment within the tissue [10,11], atherosclerosis continues with inflammatory cell infiltration and foam cell accumulation [12], whereas aortic valve disease follows these events down a pathway culminating in leaflet calcification [13,14]. The vascular neointima, which forms following smooth muscle cell migration and proliferation and matrix secretion and where the atherosclerotic plaque develops [12], does not have an anatomical equivalent in CAVD; this may be a defining factor regarding the later progression of the respective diseases. Furthermore, in contrast to the phenomena of vSMC proliferation in atherosclerosis, cell proliferation does not appear to be a major factor in CAVD [15,16]. It should be noted, however, that there is appreciable overlap between CAVD and coronary artery disease [5]. Up to 50% of patients with CAVD have coronary artery disease [17].

Addressing risk factors such as hypertension, dyslipidemia and diabetes through lifestyle and therapeutic interventions can clearly change the course of atherosclerosis; some of these same risk factors are associated with CAVD [5,17]. The obvious potential of atherosclerosis-directed risk factor strategies, such as the use of anti-hypertensive agents and statins, has been explored for valvular applications, but the clinical trial results have been equivocal. Specifically, a high dose statin regime did not prevent CAVD under conditions in which it would most likely have prevented adverse vascular events [18] yet more recently a second prospective study with rosuvastatin slowed the progression of CAVD [19]. What is required is an understanding of the pathology of CAVD at a biochemical and cellular level for comparison with atherosclerosis. If a common early pathological step can be determined, then early therapy may be concomitantly preventative for atherosclerosis driven vascular disease and sclerotic aortic valve disease, preventing the progression of the latter to calcification and stenosis. Recent evidence strongly implicates the trapping of lipoproteins by extracellular matrix, specifically proteoglycans, in the development of atherosclerosis. Nakashima et al. demonstrated that early human atherosclerosis commences with the deposition of LDL associated with the proteoglycan biglycan [20]. It has been proposed that therapeutic modifications that reduce the "stickiness" of proteoglycans might mitigate atherosclerosis [10,21]. Furthermore, the role of the glycosaminoglycan (GAG), hyaluronan (HA), in the attraction and accumulation of monocytes in atherosclerosis suggests an intriguing possibility of a role for these GAGs in the chronic inflammation of valve disease [22,23]. Glycosaminoglycans have been extensively studied in bioprosthetic [24] and myxomatous valves [25] but have received little attention in the pathology of CAVD. This review examines the role of proteoglycan-associated GAGs and "free" hyaluronan in the lipid retention and inflammatory phase of aortic valve disease from the point of view that there may be pathological processes associated with GAG synthesis and structure that represent common therapeutic targets in atherosclerosis and CAVD. Numerous terms have been used for the quantitatively predominant cell type present in aortic valve leaflets and for consistency we use the term aortic valve myofibroblasts (avMs) in this review because these cells have the morphological properties of fibroblasts and stain positively for smooth muscle {alpha}-actin.


   2. Current understanding of the development of aortic valve disease
Top
 Abstract
 1. Introduction
 2. Current understanding of...
3. Galactosaminoglycan fine...
 4. Regulation of HA...
 5. Pharmacological and...
 6. Conclusions
 References
 
The factors that initiate the process of aortic valve disease have not been clearly identified, but it is recognized as having similar features to early atherosclerosis [20] including the co-localization of lipids with the proteoglycans biglycan and decorin [26,27]. Lipids, oxidized lipids, lipoproteins (LDL and Lp(a)), and cholesterol are present in lesions of human sclerotic and stenotic aortic valves, as well as in the underlying collagenous fibrosa [2,15,28,29], within regions characterized by elastic lamina fragmentation, macrophages, and accumulation of GAGs and proteoglycans [26–28]. The proteins apoB, apo(a), and apoE have also been found in valve lesions and/or in the adjacent fibrosa [27,29]. Key differences between aortic valve disease and atherosclerosis are the deposition of lipid in the sub-endothelial fibrosa layer in aortic valves, not in deeper layers, and calcification instead of necrosis as a response to lipid trapped in the valvular tissue [4,27,29]. The signals that follow lipid deposition will be of significant importance to unraveling the pathogenesis of calcific aortic valve stenosis. Animal models, such as hypercholesterolemic rabbits [30], have been employed to demonstrate that hyperlipidemia results in a sclerotic valve that mineralizes and stenoses over time [3].

Despite the clear role of lipid retention and accumulation in the early stages of aortic valve stenosis, to date there is little evidence that the lipid-lowering statins prevent CAVD, although they may reduce its progression. In experimental hypercholesterolemic rabbits, atorvastatin reduced serum cholesterol and several osteoblast gene markers [31] and inhibited calcification via upregulation of eNOS [32], indicating that statins are able to restrict the transformation of avMs to osteoblast-like cells and thereby affect more than lipid-lowering. Indeed, hypercholesterolemic aortic valve calcification mediated by the low density receptor-related protein Lrp5 can be reduced by atorvastatin [33,34]. Lrp binds to the secreted glycoprotein Wnt (a key regulator of bone formation) and frizzled receptors that subsequently activate β-catenin as part of the canonical Wnt/β-catenin signaling pathway in bone mineralization [35]. Statins inhibit calcific nodule formation in cultured porcine avMs via inhibition of cholesterol synthesis in a protein prenylation-independent manner [36]. Human avMs show a significant reduction in osteoblastic differentiation after atorvastatin treatment [37]. Clinically, retrospective studies (reviewed in [38]) and a prospective study [19] have shown that statins reduce progression of aortic valve stenosis and calcification but have limited preventative value for this condition.

There is substantial evidence that calcific aortic valve disease involves inflammatory processes. Lesions from early sclerosis as well as from advanced calcific stenosis contain macrophages, T-lymphocytes, and mast cells [15,39]. VCAM-1, which is not normally expressed in aortic valve leaflets, is expressed on the endothelium of calcific aortic valves [40]. Several inflammatory cytokines, including IL-2, HLA-DR, IL-1β, TNF-{alpha} (for review see [2]), and c-reactive protein [41] are also present in valve lesions. Inflammation has also been demonstrated by elevated expression of matrix metalloproteinases (MMPs) and their tissue inhibitors within sclerotic and stenotic aortic valves, although there is conflicting data on their abundance [2,42,43].

The presence of growth factors such as TGF-β in valve lesions is particularly noteworthy since growth factors influence cell proliferation, migration and protein synthesis and affect several different pathways, including calcification. In fact, TGF-β was found to be more abundant within the matrix of calcified valves than in non-calcified sclerotic valves and in the presence of TGF-β, avMs undergo aggregation, increased alkaline phosphatase activity, apoptosis and calcific nodule formation [43,44]. The aortic valve tissue response to injury is similar to other tissues with initial elevated TGF-β levels that have been shown in avMs in vitro to increase SM {alpha}-actin expression, stress fibre formation, contraction, collagen and HA synthesis, and secretion of sulfated GAGs [45]. TGF-β can signal through several pathways classically via high affinity binding to TGF-βRII which recruits ALK5 (TGF-βRI) to form a heterodimeric complex. Ser/Thr phosphorylation of ALK5 by TGF-βRII enables ALK5 phosphorylation of the carboxy terminal Ser residues of the intracellular signal transducers SMAD-2 and -3. Phospho-SMADs form complexes with SMAD-4 and are translocated to the nucleus where they bind to elements in target gene promoter regions inducing gene activation or repression. TGF-β is also able to activate ERK, JNK and p38 MAP-kinases, Rho-like kinases, PI3 kinase and protein phosphatase PP2a in both SMAD-dependent and independent manners [46]. The specific TGF-β pathways in avMs and particularly those participating in CAVD have yet to be elucidated.

Although fibroblast growth factors (FGFs) have not yet been reported in sclerotic or stenotic aortic valves, FGF-2 and the FGF-receptor 1 have been demonstrated in mitral valvular myofibroblasts in vitro, where they are strongly expressed in migrating cells [47]. FGF has also been shown to be a potent activator of remodelling and collagen synthesis by avMs grown in three-dimensional culture, more so than TGF-β [48]. Given that FGF-1 and FGF-2 similarly promote vSMC migration, proliferation, and biosynthesis, predominantly via activation of FGFR-1 and FGFR-2, that these growth factors and their receptors are abundantly expressed throughout atherosclerotic plaques, and that inhibition of FGFR-1 in hypercholesterolemic apoE null mice reduced lesion size, PCNA+ cells, and MCP-1 [49] suggests that FGFs and FGFRs may play a common role in diseased aortic valves.

Diseased aortic valves exhibit distinctive changes in their ECM. Lipid-rich lesions accumulate predominately on the aortic surface of the valve [15]; the basement membrane/elastic lamina beneath these lesions appears to be damaged or absent. The collagenous fibrosa becomes thickened [15], partially due to the infiltration of lipids. Specific proteoglycans (biglycan, decorin, and versican) have increased abundance in early through late aortic valve lesions; biglycan and decorin are colocalized with apoE and apoB [26,27].

Angiotensin peptides (I and II), enzymes, and receptors also contribute to the development of aortic valve sclerotic lesions [2]. Angiotensin converting enzyme (ACE) and angiotensin II are colocalized with ApoB in valve lesions [50]. The angiotensin-1 receptor, not normally expressed in heart valves, is present in these lesions and its activation can increase the production of oxidants and proteoglycans. Moreover, there is in vitro evidence that these peptides can be synthesized within the valve [51].

The deposition of calcific nodules is a hallmark of the advanced valvular sclerotic lesion and causes the leaflets to become stiff and the valve stenotic. These nodules are found in association with oxidized lipids both in human valves and in animal models. Calcific leaflets also contain osteoblast-like cells [39] and an abundance of several osteogenic mediators, including osteopontin, osteocalcin, BMPs 2 and 4, TGF-β, tenascin-C, alkaline phosphatase, and MMP2 [43,47]. In vitro, avMs in prolonged culture will spontaneously form calcific nodules, particularly upon addition of 25-hydroxycholesterol and TGF-β [44]. avMs exposed to elevated cyclic pressures (in a model of hypertension, a common risk factor for aortic valve stenosis) downregulate the expression of osteopontin; since this agent is protective against mineralization, its downregulation may potentiate calcification [52]. The osteogenic mediators BMP-2 and -4 are part of the TGF-β superfamily and like TGF-β utilize the intracellular SMAD proteins to target gene regulation [53]. Through this pathway BMP-2 upregulates the osteoblast differentiation core binding factor alpha Cbfa1/Runx2. Interestingly both TGF-β and BMP-2 rely on a SMAD-4-containing heterocomplex to translocate their respective signals to the nucleus and this may provide a potential pivot point in the signaling cascades where competing signals result in an imbalance that leads to valvular calcification. Recently Garg et al. [54] demonstrated a genetic component in familial aortic valve disease with mutations of the signaling molecule NOTCH1 resulting in repression of Cbfa1/Runx2 and activation of osteoblast-specific gene expression with consequent aortic valve calcification. Additionally, it has been demonstrated in Xenopus that both TGF-β and BMP-4 bind to different domains of the proteoglycan biglycan and that a consequence of BMP-4 binding is regulation of BMP-4 activity. It is not yet known how this functional relationship impacts osteogenesis [55], however, it does raise intriguing possibilities for the involvement of biglycan, TGF-β and BMP signaling cascades in the pathogenesis of aortic valve stenosis.

If the trapping of apolipoproteins by proteoglycans is a critical initiating step in aortic valve pathophysiology, then an understanding of the properties of valve proteoglycans (specifically their GAG chains) and their regulation will be critical in disease prevention. Similarly, if hyaluronan plays a role in aortic valve disease, then the regulation of its synthesis, structure, and ability to bind inflammatory cells will be important. A hypothetical scheme showing the interrelationships of the above factors and specifically the potential role of proteoglycans and HA in the initiation, development and progression of CAVD is shown in Fig. 1.


Figure 1
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  		Fig. 1 A schema showing the possible steps in the early development of Calcific Aortic Valve Disease based on a consideration of the similarities with atherogenesis. The scheme focuses on the potential role of glycosaminoglycans as part of proteoglycans in the entrapment of LDL participles and as hyaluronan in the recruitment and subsequent infiltration of inflammatory cells (heavy black dotted arrows). Valve disease has a greater propensity (compared to atherosclerosis) to progress to a calcification stage as indicated.

 

   3. Galactosaminoglycan fine structure and lipoprotein binding
Top
 Abstract
 1. Introduction
 2. Current understanding of...
 3. Galactosaminoglycan fine...
4. Regulation of HA...
 5. Pharmacological and...
 6. Conclusions
 References
 
With the exception of hyaluronan, all GAGs exist in vivo as components of proteoglycans; a proteoglycan consists of a core protein covalently linked to at least one GAG chain. The major GAGs associated with cardiovascular tissues are the glucosaminoglycans on heparan sulfate proteoglycans and the galactosaminoglycans on the chondroitin and dermatan sulfate proteoglycans decorin, biglycan, and versican [56]. All of these proteoglycans, as well as all four classes of GAGs, have been found in varying abundance in heart valves (Table 1 and Fig. 2) [15,57]. The three structural properties of galactosaminoglycan chains that can potentially influence the binding to apolipoproteins on LDL particles are chain length, the extent and pattern of sulfation, and the isoform of the uronic acid moiety on the GluA [21,58]; each of these can be modulated.


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  		Table 1 Proteoglycans/GAGs of human aortic valves

 

Figure 2
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  		Fig. 2 Repeating disaccharide units and possible sulfation positions of glycosaminoglycan chains (GAGs, composed of disaccharides) of aortic valve proteoglycans (core protein covalently linked to at least one GAG chain) and glycosaminoglycans. The major GAGs associated with aortic valves are the glucosaminoglycans on heparan sulfate proteoglycans and the galactosaminoglycans on the chondroitin sulfate (CS) and dermatan sulfate (DS) proteoglycans decorin, biglycan, and versican.

 
3.1 Galactosaminoglycan chain length as a determinant of lipoprotein binding
Proteoglycans are synthesized in a range of sizes that appear as a smear when analysed by SDS-PAGE [21]. As the size of the core protein is fixed, this variation arises from the range of sizes of the galactosaminoglycan chains. There is vast evidence demonstrating that longer galactosaminoglycan chains exhibit enhanced binding to LDL particles. This can be demonstrated for intact proteoglycans, free galactosaminoglycan chains and so-called xyloside galactosaminoglycans although the affinity of the interaction varies markedly [59]. Galactosaminoglycan chains bound to proteoglycan core proteins show higher affinity binding to LDL compared to free chains due to thermodynamic considerations of molecular rigidity. As a marked example of the impact of size on binding, the considerably shorter galactosaminoglycan chains synthesized in in vitro experiments on exogenous xyloside bind LDL with almost one order of magnitude lower affinity [59]. When proteoglycan and xyloside galactosaminoglycans are derived from vSMCs treated with TGF-β, the chains are longer and the binding to LDL is enhanced [59]. Although some growth factors alter the sulfation pattern as well as cause galactosaminoglycan chain elongation, TGF-β only alters galactosaminoglycan size, therefore the demonstrated LDL-binding relationship appears to depend entirely on galactosaminoglycan size [60].

3.2 Sulfation extent and pattern
Sulfation pattern is critical for the determination of the biological actions of GAGs. Sulfation determines the mitogenic action of heparan sulfate oligosaccharides [61] and more recently it has been demonstrated to be a determinant of the biological action of chemically synthesized chondroitin sulfate oligosaccharides [62]. Sulfation is also critical for the ionic interaction between galactosaminoglycans and LDL, in which subtle changes in sulfation can alter the interaction, but that relationship is far less understood. The major sulfation positions on galactosaminoglycan disaccharides are the 4 and 6 positions on the N-acetyl galactosamine and the 2 position on the GluA (see Fig. 2). The 6-sulfate group on the GalNAc is exocyclic and thus more sterically accessible to the binding sites on LDL. The 4-sulfate is endocyclic and less sterically accessible; although the overall ionic charge on the two molecules is identical, it is possible that the 4-sulfate causes an altered peak charge density, which could also lead to enhanced LDL binding (Fig. 2). The Golgi location of each sulfotransferase dictates that the 6-sulfate is added prior to the 4-sulfate and growth factors such as PDGF increase the 6-sulfated product [60]; avMs also synthesize substantial amounts of 4-sulfated and 6-sulfated products [63]. It will be important to determine if the action of vasoactive growth factors to alter the sulfation pattern is a pro-atherogenic and potentially pro-sclerotic in CAVD and moreover if the signalling pathways for elongation and sulfation are identical or coordinated in terms of the need to block both pathways to reduce atherogenic changes to the galactosaminoglycan chains [21,64].

3.3 Uronic acid isoform
The 5-position carboxylic acid group of GluA is synthesized in the glucuronic acid isoform of a chondroitin sulfate galactosaminoglycan but is subject to isomerisation, generating the iduronic acid derivative and thus the dermatan sulfate galactosaminoglycan [65] (Fig. 2). These isomers display different levels of structural flexibility and potentially different ionic charge distributions, both of which may determine LDL binding [66]. Compared to the glucuronic acid isoform, the iduronic acid form provides a more rigid structure, which thermodynamic considerations would suggest is associated with enhanced binding to LDL. In addition, there is a tight coupling between isomerisation and 4-sulfation that may influence LDL binding [67]. Clearly, more detailed work is required in this area but as the isomerase activity is highly regulated, the recent molecular identification of the enzyme should create research opportunities in this area [68].


   4. Regulation of HA in atherosclerosis and potential association with AV disease
Top
 Abstract
 1. Introduction
 2. Current understanding of...
 3. Galactosaminoglycan fine...
 4. Regulation of HA...
5. Pharmacological and...
 6. Conclusions
 References
 
If the early mechanisms of AV disease and atherosclerosis are indeed similar, the GAG hyaluronan may be part of an additional avenue for the development and treatment of valvular sclerosis. HA is normally abundant within heart valves (particularly in the spongiosa layer), can account for up to 50–60% of all valve GAGs [25,57], and is measurably released by avMs [43,63]. Although the role of HA, HA receptors, and HA turnover in valve sclerosis is presently unknown, HA is abundant in atherosclerotic lesions, particularly surrounding SMCs and macrophages [69]. In vitro, HA facilitates the proliferation and migration of SMCs and leukocytes [69,70]. Proliferating SMCs and fibroblasts likewise synthesize more HA [70], often as cables that bind and retain monocytes [71]. avMs treated with TGF-β also upregulate HA production [43]. As described previously, atherosclerotic lesions stain strongly for TGF-β, as well as for PDGF-AB [69]; both have been shown to regulate HA synthesis by numerous cell types [72].

The signaling pathways regulating the activity of the hyaluronan synthases, three isozymes known as HAS-1, HAS-2, and HAS-3, also represent therapeutic targets for atherosclerosis and potentially for CAVD. Ligation of FGF receptors with FGF induces HAS expression: when apoE-null mice fed a high fat diet were treated with FGFR inhibitors, HAS-1 and HAS-2 expression was reduced and the expression of the oxidized LDL receptor CD36 was reduced [49]. Recently the expression of HAS2 in mouse AV leaflets has been reported [73]. These synthases can be controlled by statins: it was recently reported that HAS-2 expression was markedly inhibited in ApoE deficient mice treated with rosuvastatin [74].

Regulation of HA and its effects might also be mediated through its several specific receptors on the cell surface, including CD44, RHAMM (the receptor for hyaluronic acid mediated motility), and stabilin-2 or HARE (HA receptor for endocytosis). HA ligation to CD44 mediates leukocyte, monocyte, and macrophage recruitment, the production of inflammatory mediators IL-12, MCP-1, and iNOS, and vascular cell activation [71,75]. Binding of HA to CD44 causes tyrosine kinase activity of p185HER-2 and src and the activation of Rho and Rac-1; binding of HA to RHAMM activates downstream signaling via src and Ras [71]. Furthermore, ligation of RHAMM modifies the ability of the PDGF receptor to activate ERK kinase. CD44 has been found in the heart valves of adult mice [76]; RHAMM has not been investigated in the context of valves. Stabilin-2, the receptor involved in clearance of HA and selected galactosaminoglycan proteoglycans, shows strong expression in murine heart valves [77]. Even in vitro, avMs have been shown to regulate their proliferation and protein synthesis when supplemented with different molecular fragments of HA [78]. In blood vessels, CD44 is up-regulated after injury in vivo [79]. It is speculated that HA accumulation near the luminal surface destabilizes the local endothelial cells, resulting in CD44-dependent platelet adhesion [80]. When SMCs become activated, the upregulated CD44 stimulates and facilitates their proliferation and migration.

As do sulfated GAGs, HA also demonstrates the ability to retain lipids [75,81], leading to the development of lipid-rich lesions. Seike et al. recently demonstrated that cholesterol-lipoprotein binding and macrophage uptake of LDL were directly proportional to the dose of incorporated HA or chondroitin 6-sulfate [81]. Furthermore, macrophage uptake of LDL was not blocked by saturation of the HA receptors with excess HA, but was completely blocked by an antibody against the macrophage scavenger receptor CD204. In a model of xanthoma, a sclerotic dermal lesion, intradermal injections of HA into the skin of hyperlipidemic rabbits attracted macrophages that turned into foam cells, and cholesterol was accumulated at the site. Injection of chondroitin 6-sulfate produced a similar effect, implying that the retention of lipoproteins by complex formation with GAGs is a promoting factor in xanthoma formation and supporting the response to retention hypothesis [81]. With respect to atherosclerosis, Cuff et al. showed that CD44-null mice crossed with apo-E null mice had less atherosclerosis than the uncrossed apo-E null mice, despite equivalent cholesterol levels [75]. These models demonstrate that CD44 is required for maximal VCAM-1 upregulation and macrophage recruitment. In vitro, the addition of low molecular weight HA caused a CD44-dependent upregulation of SMC proliferation (an effect also reported in avMs [78]) and VCAM-1 synthesis [75]. The role of HA in upregulating VCAM-1 expression appeared partly dependent on NF{kappa}B activation, which also influences macrophage recruitment; other HA receptors may also be involved in early lesion development [75]. Overall, the relationship between HA, its receptors, and vSMC phenotype in atherosclerosis is demonstrably strong and can be mitogenically or pharmacologically manipulated [71].

Finally, the potential role for HA in the development of calcific AV disease is supported by findings that selected patient populations, such as those with diabetes, have greater risk for this disease [6]. For example, serum levels of HA, in correlation with several atherosclerotic markers such as MCP-1, were reportedly twice as high in diabetics as in normal subjects [82]. Animal models of diabetes also showed significant upregulation of HA and hyaluronidase (which generate low molecular weight HA fragments) following vascular injury [83]. Taken together, the various factors that promote the formation of an HA-rich matrix likely regulate lesion development and inflammatory responses in heart valves as well as vessels.


   5. Pharmacological and therapeutic regulation of proteoglycan-associated GAG synthesis and structure
Top
 Abstract
 1. Introduction
 2. Current understanding of...
 3. Galactosaminoglycan fine...
 4. Regulation of HA...
 5. Pharmacological and...
6. Conclusions
 References
 
As is the case with hyaluronan, proteoglycans and their GAG chains are highly influential in atherogenesis; several reviews on this topic are available [21,84]. Although many of these same proteoglycans and GAGs are found in heart valves, and are the subject of several in vitro reports [63,78], proteoglycan and GAG investigations in the field of heart valves do not yet address lesion development in great depth.

Much of the work on the regulation of GAG synthesis is available from studies in vSMCs as there appears to be very little work in this area available on avMs. However, the receptors on avMs are potentially similar to those on vSMCs and it is likely that common mechanisms will emerge [85]. A wide and increasing range of factors are known to stimulate GAG synthesis in vSMCs. Although cell cycling stimulates GAG synthesis, many agonists clearly act independently of their proliferative effects. Atherogenic stimuli such as the tyrosine kinase receptor agonist PDGF [60] and serine/threonine growth factor TGF-β [59,60] are both able to stimulate the elongation of GAG chains. PDGF, but not TGF-β, stimulates an increase in sulfation at the potentially atherogenic 6-position indicating that the signalling pathways controlling GAG chain length and sulfation are independent. The seven transmembrane receptor agonist angiotensin II stimulated GAG elongation as well as an increase in the dermatan to chondroitin ratio, the latter implying an activation of the isomerase enzyme [86]; similar receptor agonists such as endothelin, thrombin and urotensin might similarly activate GAG synthesis. Metabolic factors, such as free fatty acids and oxidised LDL, can also activate GAG synthesis leading to GAG elongation [87,88]. Cell-matrix adhesions also influence GAG synthesis by vSMCs, although the close link between matrix components and cell proliferation complicates the elucidation of this relationship [89].

Although the signalling pathways that affect GAG synthesis are largely uncharted, they clearly represent avenues for developing inhibitors that could be therapies for coronary artery disease and CAVD. Intriguingly, the ability of PDGF to stimulate GAG elongation in vSMCs is not blocked by the PDGF receptor tyrosine kinase inhibitor genistein even at a high concentration that clearly blocks the effect of PDGF on proliferation and core protein synthesis [64], indicating that the classic PDGF proliferation pathway is not the pathway leading to GAG elongation. PDGF also stimulates 6-sulfation in vSMCs and, similarly to the elongation pathway, this pathway is also not blocked by genistein (Ballinger and Little, unpublished observation). Thus the signalling pathway by which PDGF mediates its effects on GAG synthesis appears to be novel and worthy of further investigation, particularly in the context of calcific AV disease.

The process by which GAGs are modified is inhibitable by pharmacological intervention [90,91]. In some cases the inhibitors are those which block either cell surface receptors or known intracellular signalling pathways, whereas others represent the pleiotropic actions of cardiovascular drugs without a demonstrated mechanism of action. Numerous agents including the calcium antagonist amlodipine [91], the PPAR{alpha} ligands gemfibrozil [92] and fenofibrate [90] and PPAR{delta} ligands troglitazone, rosiglitazone and pioglitazone [93] all inhibit GAG elongation in vSMCs and reduce proteoglycan binding to LDL [92,94]. These actions represent "pleiotropic" or supplementary actions of these agents and none is potent or highly efficacious in its own right. The lack of an unambiguous mechanism is apparent from the studies with calcium channel blockers in which two stereoisomers, only one of which is a calcium channel antagonist, have equal potency and efficacy in blocking proteoglycan synthesis [91]. Even in the absence of a mechanism it is possible that these actions of cardiovascular drugs may be important since they have been shown to reduce the development of atherosclerosis in animal models and some have even been beneficial in clinical trails [95]. Clearly, considerable work is required to determine agonist and antagonist profiles in avMs as well as the signalling pathways that mediate changes in GAG structure with a view to assessing the potential commonality of sclerotic pathways in vSMCs and avMs.


   6. Conclusions
Top
 Abstract
 1. Introduction
 2. Current understanding of...
 3. Galactosaminoglycan fine...
 4. Regulation of HA...
 5. Pharmacological and...
 6. Conclusions
References
 
The synthesis and structure of GAGs represents a potential target for the prevention and treatment of CAVD with a concomitant and beneficial action to prevent atherosclerosis-related coronary and peripheral artery disease. There are similarities in the development of disease in blood vessels and heart valve leaflets, particularly the early accumulation of lipids. If it can be demonstrated that the modifications of GAG synthesis and structure are early changes that are common to both disease processes, then there could be a benefit of novel therapies suitable for the treatment of both pathologies.

It has recently been appreciated that the synthesis of GAGs is a highly active and regulated process and that the turnover of GAGs in the vessel wall is sufficiently high to render this process as a potential therapeutic target [21]. Furthermore, a range of cardiovascular agents have the pleiotropic capability to inhibit the synthesis of GAGs on vascular proteoglycans, to prevent lipid binding in vitro, and to prevent atherosclerosis in animal models. Some of these agents also inhibit hyaluronan synthesis, which may represent a novel anti-inflammatory action (Nigro, Little and Wight, unpublished observations).

Collectively, the documented abundance of PGs and HA in calcific aortic valves and the roles of these matrix components in atherosclerosis provide a compelling opportunity to develop mechanistically based agents that inhibit the structural changes in GAGs and consequently to prevent the lipid binding and monocyte infiltration that appear to be critical early events in calcific AV disease as well as in atherosclerosis. The ultimate outcome would be to utilize a risk factor directed strategy, such as ACE inhibitors for hypertension, statins for dyslipidemia or glitazones in the presence of diabetes, along with a mechanistic agent such as an inhibitor of proteoglycan or hyaluronan synthesis to affect a major reduction in these important cardiovascular diseases.

Time for primary review 27 days


   Acknowledgement
 
We thank the Human Frontiers Science Program for funding a short term travel fellowship to allow JGA to spend time in the laboratory of PJL, which served as the initial stimulus for this collaborative review. Recent work in the laboratory of PJL has been supported by the National Health and Medical Research Council and the National Heart Foundation. We thank A. Holmes for assistance with the preparation of Fig. 1.


   References
Top
 Abstract
 1. Introduction
 2. Current understanding of...
 3. Galactosaminoglycan fine...
 4. Regulation of HA...
 5. Pharmacological and...
 6. Conclusions
 References
 

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