bims-supasi Biomed News
on Sulfation pathways and signalling
Issue of 2023–01–29
seven papers selected by
Jonathan Wolf Mueller, University of Birmingham
  1. Scaffolds containing GAG-mimetic cellulose sulfate promote TGF-β interaction and MSC Chondrogenesis over native GAGs.
  2. Design of an Ultralow Molecular Weight Heparin That Resists Heparanase Biodegradation.
  3. Regulation of autophagy, lipid metabolism, and neurodegenerative pathology by heparan sulfate proteoglycans.
  4. The association between a genetic variant in the SULF2 gene, metabolic parameters and vascular disease in patients at high cardiovascular risk.
  5. The kidney drug transporter OAT1 regulates gut microbiome-dependent host metabolism.
  6. Age-related decrease in serum dihydrotestosterone concentration is accompanied by impaired vascular status.
  7. Heparin and heparin proteoglycan-mimetics activate platelets via PEAR1 and PI3Kβ.
  1. J Biomed Mater Res A. 2023 Jan 27.
    Scaffolds containing GAG-mimetic cellulose sulfate promote TGF-β interaction and MSC Chondrogenesis over native GAGs.
    Roseline Menezes, Lauren Sherman, Pranela Rameshwar, Treena Livingston Arinzeh.
      Cartilage tissue engineering strategies seek to repair damaged tissue using approaches that include scaffolds containing components of the native extracellular matrix (ECM). Articular cartilage consists of glycosaminoglycans (GAGs) which are known to sequester growth factors. In order to more closely mimic the native ECM, this study evaluated the chondrogenic differentiation of mesenchymal stem cells (MSCs), a promising cell source for cartilage regeneration, on fibrous scaffolds that contained the GAG-mimetic cellulose sulfate. The degree of sulfation was evaluated, examining partially sulfated cellulose (pSC) and fully sulfated cellulose (NaCS). Comparisons were made with scaffolds containing native GAGs (chondroitin sulfate A, chondroitin sulfate C and heparin). Transforming growth factor-beta3 (TGF-β3) sequestration, as measured by rate of association, was higher for sulfated cellulose-containing scaffolds as compared to native GAGs. In addition, TGF-β3 sequestration and retention over time was highest for NaCS-containing scaffolds. Sulfated cellulose-containing scaffolds loaded with TGF-β3 showed enhanced chondrogenesis as indicated by a higher Collagen Type II:I ratio over native GAGs. NaCS-containing scaffolds loaded with TGF-β3 had the highest expression of chondrogenic markers and a reduction of hypertrophic markers in dynamic loading conditions, which more closely mimic in vivo conditions. Studies also demonstrated that TGF-β3 mediated its effect through the Smad2/3 signaling pathway where the specificity of TGF-β receptor (TGF- βRI)-phosphorylated SMAD2/3 was verified with a receptor inhibitor. Therefore, studies demonstrate that scaffolds containing cellulose sulfate enhance TGF-β3-induced MSC chondrogenic differentiation and show promise for promoting cartilage tissue regeneration.
    Keywords:  cellulose; chondrogenesis; chondroitin sulfate; glycosaminoglycans; mesenchymal stem cells
    DOI:  https://doi.org/10.1002/jbm.a.37496
  2. J Med Chem. 2023 Jan 27.
    Design of an Ultralow Molecular Weight Heparin That Resists Heparanase Biodegradation.
    Hyunok Ham, Yongmei Xu, Carolyn A Haller, Erbin Dai, Eduardo Stancanelli, Jian Liu, Elliot L Chaikof.
      Heparanase, an endo-β-d-glucuronidase produced by a variety of cells and tissues, cleaves the glycosidic linkage between glucuronic acid (GlcA) and a 3-O- or 6-O-sulfated glucosamine, typified by the disaccharide -[GlcA-GlcNS3S6S]-, which is found within the antithrombin-binding domain of heparan sulfate or heparin. As such, all current forms of heparin are susceptible to degradation by heparanase with neutralization of anticoagulant properties. Here, we have designed a heparanase-resistant, ultralow molecular weight heparin as the structural analogue of fondaparinux that does not contain an internal GlcA residue but otherwise displays potent anticoagulant activity. This heparin oligosaccharide was synthesized following a chemoenzymatic scheme and displays nanomolar anti-FXa activity yet is resistant to heparanase digestion. Inhibition of thrombus formation was further demonstrated after subcutaneous administration of this compound in a murine model of venous thrombosis. Thrombus inhibition was comparable to that observed for enoxaparin with a similar effect on bleeding time.
    DOI:  https://doi.org/10.1021/acs.jmedchem.2c02118
  3. Front Genet. 2022 ;13 1012706
    Regulation of autophagy, lipid metabolism, and neurodegenerative pathology by heparan sulfate proteoglycans.
    Nicholas Schultheis, Robert Becker, Gelila Berhanu, Alexander Kapral, Matthew Roseman, Shalini Shah, Alyssa Connell, Scott Selleck.
      Heparan sulfate modified proteins or proteoglycans (HSPGs) are an abundant class of cell surface and extracellular matrix molecules. They serve important co-receptor functions in the regulation of signaling as well as membrane trafficking. Many of these activities directly affect processes associated with neurodegeneration including uptake and export of Tau protein, disposition of Amyloid Precursor Protein-derived peptides, and regulation of autophagy. In this review we focus on the impact of HSPGs on autophagy, membrane trafficking, mitochondrial quality control and biogenesis, and lipid metabolism. Disruption of these processes are a hallmark of Alzheimer's disease (AD) and there is evidence that altering heparan sulfate structure and function could counter AD-associated pathological processes. Compromising presenilin function in several systems has provided instructive models for understanding the molecular and cellular underpinnings of AD. Disrupting presenilin function produces a constellation of cellular deficits including accumulation of lipid, disruption of autophagosome to lysosome traffic and reduction in mitochondrial size and number. Inhibition of heparan sulfate biosynthesis has opposing effects on all these cellular phenotypes, increasing mitochondrial size, stimulating autophagy flux to lysosomes, and reducing the level of intracellular lipid. These findings suggest a potential mechanism for countering pathology found in AD and related disorders by altering heparan sulfate structure and influencing cellular processes disrupted broadly in neurodegenerative disease. Vertebrate and invertebrate model systems, where the cellular machinery of autophagy and lipid metabolism are conserved, continue to provide important translational guideposts for designing interventions that address the root cause of neurodegenerative pathology.
    Keywords:  autophagy; co-receptors; heparan sulfate; lipid metabolism; mitochondria; nicastrin; presenilin; proteoglycans
    DOI:  https://doi.org/10.3389/fgene.2022.1012706
  4. Cardiovasc Endocrinol Metab. 2023 Mar;12(1): e0278
    The association between a genetic variant in the SULF2 gene, metabolic parameters and vascular disease in patients at high cardiovascular risk.
    Britt E Heidemann, Frank Lj Visseren, Jessica van Setten, A David Marais, Charlotte Koopal.
      Clearance of triglyceride-rich lipoproteins (TRLs) is mediated by several receptors, including heparan sulfate proteoglycans (HSPGs). Sulfate glucosamine-6-O-endosulfatase-2 is a gene related to the regulation of HSPG. A variant in this gene, rs2281279, has been shown to be associated with triglycerides and insulin resistance.
    Objective: To determine the relationship between rs2281279, metabolic parameters and vascular events, and type 2 diabetes mellitus (T2DM) in patients at high cardiovascular risk and whether APOE genotype modifies this relationship.
    Methods: Patients (n = 4386) at high cardiovascular risk from the Utrecht Cardiovascular Cohort-Second Manifestations of Arterial Disease study were stratified according to their imputed rs2281279 genotype: AA (n = 2438), AG (n = 1642) and GG (n = 306). Effects of rs2281279 on metabolic parameters, vascular events and T2DM were analyzed with linear regression and Cox models.
    Results: There was no relationship between imputed rs2281279 genotype and triglycerides, non-high-density lipoprotein (HDL)-cholesterol, insulin and quantitative insulin sensitivity check index. During a median follow-up of 11.8 (IQR, 9.3-15.5) years, 1026 cardiovascular events and 320 limb events occurred. The presence of the G allele in rs2281279 did not affect the risk of vascular events [hazard ratio (HR), 1.03; 95% confidence interval (CI), 0.94-1.14] or limb events (HR, 0.92; 95% CI, 0.77-1.10). The presence of the G allele in rs2281279 did not affect the risk of T2DM (HR, 1.09; 95% CI, 0.94-1.27). The presence of the minor G allele of rs2281279 was associated with a beneficial risk profile in ε2ε2 patients, but not in ε3ε3 patients.
    Conclusions: Imputed rs2281279 genotype is not associated with metabolic parameters and does not increase the risk of vascular events or T2DM in patients at high risk for cardiovascular disease.
    Keywords:  SULF2 gene; diabetes mellitus type 2; heparan sulfate proteoglycans; single nucleotide polymorphism; triglycerides
    DOI:  https://doi.org/10.1097/XCE.0000000000000278
  5. JCI Insight. 2023 Jan 24. pii: e160437. [Epub ahead of print]8(2):
    The kidney drug transporter OAT1 regulates gut microbiome-dependent host metabolism.
    Jeffry C Granados, Vladimir Ermakov, Koustav Maity, David R Vera, Geoffrey Chang, Sanjay K Nigam.
      Organic anion transporter 1 (OAT1/SLC22A6, NKT) is a multispecific drug transporter in the kidney with numerous substrates, including pharmaceuticals, endogenous metabolites, natural products, and uremic toxins. Here, we show that OAT1 regulates levels of gut microbiome-derived metabolites. We depleted the gut microbiome of Oat1-KO and WT mice and performed metabolomics to analyze the effects of genotype (KO versus WT) and microbiome depletion. OAT1 is an in vivo intermediary between the host and the microbes, with 40 of the 162 metabolites dependent on the gut microbiome also impacted by loss of Oat1. Chemoinformatic analysis revealed that the altered metabolites (e.g., indoxyl sulfate, p-cresol sulfate, deoxycholate) had more ring structures and sulfate groups. This indicates a pathway from gut microbes to liver phase II metabolism, to renal OAT1-mediated transport. The idea that multiple gut-derived metabolites directly interact with OAT1 was confirmed by in vitro transport and magnetic bead binding assays. We show that gut microbiome-derived metabolites dependent on OAT1 are impacted in a chronic kidney disease (CKD) model and human drug-metabolite interactions. Consistent with the Remote Sensing and Signaling Theory, our results support the view that drug transporters (e.g., OAT1, OAT3, OATP1B1, OATP1B3, MRP2, MRP4, ABCG2) play a central role in regulating gut microbe-dependent metabolism, as well as interorganismal communication between the host and microbiome.
    Keywords:  Metabolism; Nephrology; Transport
    DOI:  https://doi.org/10.1172/jci.insight.160437
  6. Exp Gerontol. 2023 Jan 21. pii: S0531-5565(23)00025-6. [Epub ahead of print]173 112104
    Age-related decrease in serum dihydrotestosterone concentration is accompanied by impaired vascular status.
    Marcin Grandys, Joanna Majerczak, Marzena Frolow, Krystyna Sztefko, Stefan Chlopicki, Jerzy A Zoladz.
       INTRODUCTION: The effect of androgens on the cardiovascular system in humans is ambiguous. Moreover, still little is known about the effects of the most potent androgen, dihydrotestosterone, on arterial stiffness and endothelial function. The aim of this study was to evaluate whether age-dependent alterations in serum concentration of dihydrotestosterone and its circulating metabolite are accompanied by changes in endothelial function and arterial stiffness.
    METHODS: In 12 young and 11 older men, basal serum concentrations of testosterone, dehydroepiandrosterone sulfate (DHAE-S), androstenedione (AE), dihydrotestosterone (DHT) and androstanediol glucuronide (ADG) were analyzed in relation to vascular status including cIMT - carotid intima media thickness, cAI - central augmentation index, crPWV - carotid radial pulse wave velocity, SI - stiffness index, endothelial and inflammatory markers.
    RESULTS: Although concentration of testosterone was not different between young and older group, it was demonstrated that DHT, DHEA-S, AE and ADG were significantly lower in older men in comparison to young men (p < 0.01). Interestingly the most surprising difference was found for DHT concentration, that was as much as 61 % lower in aged men that displayed significantly higher values of cIMT, AI, crPWV and SI (p < 10-4), suggestive of arterial stiffness. Furthermore, DHT was negatively correlated to all arterial wall parameters (cAI, crPWV, SI and cIMT), c-reactive protein (CRP) and hyaluronic acid (HA) concentration, as well as positively correlated to markers of endothelial function (MNA and 6-keto-PGF1α) in all studied individuals (n = 23).
    CONCLUSIONS: We have shown that ageing leads to a significant decrease in DHT concentration that is accompanied by impaired arterial wall characteristics and worsened endothelial function. Therefore more attention should be paid to the DHT, DHEA-S and ADG concentrations as a biomarkers for vascular dysfunction in ageing men.
    Keywords:  Androgens; Cardiovascular risk; Carotid artery intima-media thickness; Endothelium; Sex steroids
    DOI:  https://doi.org/10.1016/j.exger.2023.112104
  7. J Thromb Haemost. 2023 Jan;pii: S1538-7836(22)07177-X. [Epub ahead of print]21(1): 101-116
    Heparin and heparin proteoglycan-mimetics activate platelets via PEAR1 and PI3Kβ.
    Caroline Kardeby, Alice Evans, Joana Campos, Afraa Moosa Al-Wahaibi, Christopher W Smith, Alexandre Slater, Eleyna M Martin, Sonia Severin, Alexander Brill, Gunnar Pejler, Yi Sun, Steve P Watson.
       BACKGROUND: Platelet endothelial aggregation receptor 1 (PEAR1) is a single-transmembrane orphan receptor primarily expressed on platelets and endothelial cells. Genetic variants of PEAR1 have repeatedly and independently been identified to be associated with cardiovascular diseases, including coronary artery disease.
    OBJECTIVES: We have identified sulfated fucoidans and their mimetics as ligands for PEAR1 and proposed that its endogenous ligand is a sulfated proteoglycan. The aim of this study was to test this hypothesis.
    METHODS: A heparin proteoglycan-mimetic (HPGM) was created by linking unfractionated heparin (UFH) to albumin. The ability of the HPGM, UFH and selectively desulfated heparins to stimulate platelet aggregation and protein phosphorylation was investigated. Nanobodies against the 12th to 13th epidermal growth factor-like repeat of PEAR1 and phosphoinositide 3-kinase (PI3K) isoform-selective inhibitors were tested for the inhibition of platelet activation.
    RESULTS: We show that HPGM, heparin conjugated to an albumin protein core, stimulates aggregation and phosphorylation of PEAR1 in washed platelets. Platelet aggregation was abolished by an anti-PEAR1 nanobody, Nb138. UFH stimulated platelet aggregation in washed platelets, but desulfated UFH did not. Furthermore, HPGM, but not UFH, stimulated maximal aggregation in platelet-rich plasma. However, both HPGM and UFH increased integrin αIIbβ3 activation in whole blood. By using PI3K isoform-selective inhibitors, we show that PEAR1 activates PI3Kβ, leading to Akt phosphorylation.
    CONCLUSION: Our findings reveal that PEAR1 is a receptor for heparin and HPGM and that PI3Kβ is a key signaling molecule downstream of PEAR1 in platelets. These findings may have important implications for our understanding of the role of PEAR1 in cardiovascular disease.
    Keywords:  Fucoidan; glycosaminoglycan; polysaccharides; signal transduction; sulfates
    DOI:  https://doi.org/10.1016/j.jtha.2022.10.008
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