Alterations in heparan sulfate proteoglycan synthesis and sulfation and the impact on vascular endothelial function

Pretorius, Daniëlle; Richter, Robert P.; Anand, Tanya; Cardenas, Jessica C.; Richter, Jillian R.

doi:10.1016/j.mbplus.2022.100121

Cited by 25 publications

(26 citation statements)

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“…The processes that regulate heparan sulfate synthesis are complex and highly nuanced resulting in wide permutations in both the sequencing and sulfation patterning of disaccharides that give rise to extraordinary diversity in the structural features of HSPGs expressed within the glycocalyx layer. Despite this heterogeneity, HSPG expression is highly regulated, and alterations in HSPG synthesis and sulfation can have important impact on biological functions of the glycocalyx that regulate health and disease (a topic that is reviewed in relation to the endothelial glycocalyx by Pretorius et al [4] ).…”

Section: Glycocalyx Structure and Functionmentioning

confidence: 99%

“…Many pathologic conditions result in aberrations in glycocalyx expression that, in turn, influence cellular mechanisms of disease. Changes in glycocalyx biosynthesis or post-translational structural modifications, for example, have been linked to mechanisms that disrupt anti-coagulant and anti-inflammatory properties of the vascular endothelium [4] . Furthermore, glycocalyx erosion is a hallmark of many critical illnesses, and byproducts of glycocalyx degradation can be detected in serum and measured as a marker of disease/illness severity and prognosis.…”

Section: Glycocalyx Pathobiologymentioning

confidence: 99%

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The glycocalyx: Pathobiology and repair

Richter

Sanderson

2023

Matrix Biology Plus

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Section: Glycocalyx Structure and Functionmentioning

confidence: 99%

Section: Glycocalyx Pathobiologymentioning

confidence: 99%

The glycocalyx: Pathobiology and repair

Richter

Sanderson

2023

Matrix Biology Plus

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“…HSPGs play a vital role in vascular barrier function, immune cell adhesion/tethering, hemostasis, and overall maintenance of cardiovascular homeostasis (6). In particular, 3-OS-HSPG plays an important role in regulating the anticoagulant and antiinflammatory activity of the endothelium through its interaction with AT.…”

Section: B Amentioning

confidence: 99%

“…The vascular endothelium is a key regulator of thromboinflammation through its expression of an extensive network of anticoagulant and anti-adhesive molecules (5). These include heparan sulfate proteoglycans (HSPGs), which regulate leukocyte-endothelial interactions, barrier function, and the overall anticoagulant tone of the endothelium (6,7). The biological function of HSPGs is determined, in large part, by sulfation patterns on the heparan sulfate polysaccharides (6,7).…”

Section: Introductionmentioning

confidence: 99%

“…These include heparan sulfate proteoglycans (HSPGs), which regulate leukocyte-endothelial interactions, barrier function, and the overall anticoagulant tone of the endothelium (6,7). The biological function of HSPGs is determined, in large part, by sulfation patterns on the heparan sulfate polysaccharides (6,7). In particular, heparan sulfate with the specific pentasaccharide sequence containing a central 3-O-sulfated glucosamide enables high-affinity binding to circulating antithrombin-III (AT), leading to inhibition of coagulation factor Xa and thrombin (8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%

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A 3-O-sulfated heparan sulfate dodecasaccharide (12-mer) suppresses thromboinflammation and attenuates early organ injury following trauma and hemorrhagic shock

et al. 2023

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IntroductionDysregulated inflammation and coagulation are underlying mechanisms driving organ injury after trauma and hemorrhagic shock. Heparan sulfates, cell surface glycosaminoglycans abundantly expressed on the endothelial surface, regulate a variety of cellular processes. Endothelial heparan sulfate containing a rare 3-O-sulfate modification on a glucosamine residue is anticoagulant and anti-inflammatory through high-affinity antithrombin binding and sequestering of circulating damage-associated molecular pattern molecules. Our goal was to evaluate therapeutic potential of a synthetic 3-O-sulfated heparan sulfate dodecasaccharide (12-mer, or dekaparin) to attenuate thromboinflammation and prevent organ injury.MethodsMale Sprague-Dawley rats were pre-treated subcutaneously with vehicle (saline) or dekaparin (2 mg/kg) and subjected to a trauma/hemorrhagic shock model through laparotomy, gut distention, and fixed-pressure hemorrhage. Vehicle and dekaparin-treated rats were resuscitated with Lactated Ringer’s solution (LR) and compared to vehicle-treated fresh-frozen-plasma-(FFP)-resuscitated rats. Serial blood samples were collected at baseline, after induction of shock, and 3 hours after fluid resuscitation to measure hemodynamic and metabolic shock indicators, inflammatory mediators, and thrombin-antithrombin complex formation. Lungs and kidneys were processed for organ injury scoring and immunohistochemical analysis to quantify presence of neutrophils.ResultsInduction of trauma and hemorrhagic shock resulted in significant increases in thrombin-antithrombin complex, inflammatory markers, and lung and kidney injury scores. Compared to vehicle, dekaparin treatment did not affect induction, severity, or recovery of shock as indicated by hemodynamics, metabolic indicators of shock (lactate and base excess), or metrics of bleeding, including overall blood loss, resuscitation volume, or hematocrit. While LR-vehicle-resuscitated rodents exhibited increased lung and kidney injury, administration of dekaparin significantly reduced organ injury scores and was similar to organ protection conferred by FFP resuscitation. This was associated with a significant reduction in neutrophil infiltration in lungs and kidneys and reduced lung fibrin deposition among dekaparin-treated rats compared to vehicle. No differences in organ injury, neutrophil infiltrates, or fibrin staining between dekaparin and FFP groups were observed. Finally, dekaparin treatment attenuated induction of thrombin-antithrombin complex and inflammatory mediators in plasma following trauma and hemorrhagic shock.ConclusionAnti-thromboinflammatory properties of a synthetic 3-O-sulfated heparan sulfate 12-mer, dekaparin, could provide therapeutic benefit for mitigating organ injury following major trauma and hemorrhagic shock.

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From pancreas to lungs: The role of immune cells in severe acute pancreatitis and acute lung injury

Liu,

Zhu,

Guo

2024

Immunity Inflam & Disease

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BackgroundSevere acute pancreatitis (SAP) is a potentially lethal inflammatory pancreatitis condition that is usually linked to multiple organ failure. When it comes to SAP, the lung is the main organ that is frequently involved. Many SAP patients experience respiratory failure following an acute lung injury (ALI). Clinicians provide insufficient care for compounded ALI since the underlying pathophysiology is unknown. The mortality rate of SAP patients is severely impacted by it.ObjectiveThe study aims to provide insight into immune cells, specifically their roles and modifications during SAP and ALI, through a comprehensive literature review. The emphasis is on immune cells as a therapeutic approach for treating SAP and ALI.FindingsImmune cells play an important role in the complicated pathophysiology ofSAP and ALI by maintaining the right balance of pro‐ and anti‐inflammatory responses. Immunomodulatory drugs now in the market have low thepeutic efficacy because they selectively target one immune cell while ignoring immune cell interactions. Accurate management of dysregulated immune responses is necessary. A critical initial step is precisely characterizing the activity of the immune cells during SAP and ALI.ConclusionGiven the increasing incidence of SAP, immunotherapy is emerging as a potential treatment option for these patients. Interactions among immune cells improve our understanding of the intricacy of concurrent ALI in SAP patients. Acquiring expertise in these domains will stimulate the development of innovative immunomodulation therapies that will improve the outlook for patients with SAP and ALI.

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Alterations in heparan sulfate proteoglycan synthesis and sulfation and the impact on vascular endothelial function

Cited by 25 publications

References 157 publications

The glycocalyx: Pathobiology and repair

The glycocalyx: Pathobiology and repair

A 3-O-sulfated heparan sulfate dodecasaccharide (12-mer) suppresses thromboinflammation and attenuates early organ injury following trauma and hemorrhagic shock

From pancreas to lungs: The role of immune cells in severe acute pancreatitis and acute lung injury

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