Ascorbate Reduces Mouse Platelet Aggregation and Surface P‐Selectin Expression in an <i>Ex Vivo</i> Model of Sepsis

Secor, Dan; Swarbreck, Scott; Ellis, Christopher G.; Sharpe, Michael D.; Tyml, Karel

doi:10.1111/micc.12047

Cited by 12 publications

(14 citation statements)

References 66 publications

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“…Effect of ascorbate and pH on plasminogen activator inhibitor-1 release from platelets Consistent with our report that LPS and TNFa do not affect platelet aggregation [16], LPS and TNFa did not affect PAI-1 release from platelets (Fig. 4).…”

Section: Effect Of Ascorbate On Plasminogen Activator Inhibitor-1 Prosupporting

confidence: 81%

“…Ascorbate at a concentration of 100 mmol/l did not alter the release of PAI-1 from platelets. This is in contrast to our previous report that ascorbate reduces the rate of thrombin-induced aggregation [16]. It is possible that we were unable to observe a reduction in the rate of PAI-1 release due to our inability to measure the PAI-1 content in real time.…”

Section: Effect Of Ascorbate On Plasminogen Activator Inhibitor-1 Procontrasting

confidence: 55%

“…The chosen dose of ascorbate results in physiological levels of intracellular ascorbate [15]. Thrombin (0.0375 U/ml) has been used to activate platelets to mimic sepsis ex vivo [16]. We have used this concentration of thrombin in endothelial cells as an alternative in-vitro model of sepsis.…”

Section: Animal Preparationmentioning

confidence: 99%

“…Blood was collected (9 : 1) in acid citrate dextrose solution, and platelets were isolated as detailed previously [16]. Briefly, the blood was centrifuged at 179 relative centrifugal force (rcf), and the supernatant was retained and centrifuged at 774 rcf to pellet the platelets.…”

Section: Ex-vivo Model Of Sepsis In Isolated Plateletsmentioning

confidence: 99%

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Effect of ascorbate on plasminogen activator inhibitor-1 expression and release from platelets and endothelial cells in an in-vitro model of sepsis

Swarbreck

Secor

Ellis

et al. 2015

Blood Coagulation &Amp; Fibrinolysis

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Section: Effect Of Ascorbate On Plasminogen Activator Inhibitor-1 Prosupporting

confidence: 81%

Section: Effect Of Ascorbate On Plasminogen Activator Inhibitor-1 Procontrasting

confidence: 55%

Section: Animal Preparationmentioning

confidence: 99%

Section: Ex-vivo Model Of Sepsis In Isolated Plateletsmentioning

confidence: 99%

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Effect of ascorbate on plasminogen activator inhibitor-1 expression and release from platelets and endothelial cells in an in-vitro model of sepsis

Swarbreck

Secor

Ellis

et al. 2015

Blood Coagulation &Amp; Fibrinolysis

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“…We have also used a platelet aggregation assay in vitro, to examine the role of P-selectin at the platelet surface. LPS or plasma from septic mice did not alter P-selectin expression at the platelet surface, or platelet aggregation [ 55 ]. However, platelet-activating agents known to be released into the bloodstream during sepsis [thrombin, adenosine diphosphate (ADP), thromboxane A2] did increase P-selectin expression and aggregation.…”

Section: Capillary Plugging In Sepsismentioning

confidence: 99%

Vitamin C and Microvascular Dysfunction in Systemic Inflammation

Tyml

2017

Antioxidants

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Sepsis, life-threatening organ dysfunction caused by a dysfunctional host response to infection, is associated with high mortality. A promising strategy to improve the outcome is to inject patients intravenously with ascorbate (vitamin C). In animal models of sepsis, this injection improves survival and, among others, the microvascular function. This review examines our recent work addressing ascorbate’s ability to inhibit arteriolar dysfunction and capillary plugging in sepsis. Arteriolar dysfunction includes impaired vasoconstriction/dilation (previously reviewed) and impaired conduction of vasoconstriction/dilation along the arteriole. We showed that ascorbate injected into septic mice prevents impaired conducted vasoconstriction by inhibiting neuronal nitric oxide synthase-derived NO, leading to restored inter-endothelial electrical coupling through connexin 37-containing gap junctions. Hypoxia/reoxygenation (confounding factor in sepsis) also impairs electrical coupling by protein kinase A (PKA)-dependent connexin 40 dephosphorylation; ascorbate restores PKA activation required for this coupling. Both effects of ascorbate could explain its ability to protect against hypotension in sepsis. Capillary plugging in sepsis involves P-selectin mediated platelet-endothelial adhesion and microthrombi formation. Early injection of ascorbate prevents capillary plugging by inhibiting platelet-endothelial adhesion and endothelial surface P-selectin expression. Ascorbate also prevents thrombin-induced platelet aggregation and platelet surface P-selectin expression, thus preventing microthrombi formation. Delayed ascorbate injection reverses capillary plugging and platelet-endothelial adhesion; it also attenuates sepsis-induced drop in platelet count in systemic blood. Thrombin-induced release of plasminogen-activator-inhibitor-1 from platelets (anti-fibrinolytic event in sepsis) is inhibited by ascorbate pH-dependently. Thus, under acidotic conditions in sepsis, ascorbate promotes dissolving of microthrombi in capillaries. We propose that protected/restored arteriolar conduction and capillary bed perfusion by ascorbate contributes to reduced organ injury and improved survival in sepsis.

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α1-Adrenergic Stimulation Increases Platelet Adhesion to Endothelial Cells Mediated by TRPC6

Llancalahuén

Vallejos

Aravena

et al. 2023

Advances in Experimental Medicine and Biology

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Ascorbate Reduces Mouse Platelet Aggregation and Surface P‐Selectin Expression in an Ex Vivo Model of Sepsis

Abstract: The ability of ascorbate to reduce platelet aggregation and P-selectin expression could be an important mechanism by which ascorbate inhibits capillary plugging in sepsis.

Cited by 12 publications

References 66 publications

Effect of ascorbate on plasminogen activator inhibitor-1 expression and release from platelets and endothelial cells in an in-vitro model of sepsis

Effect of ascorbate on plasminogen activator inhibitor-1 expression and release from platelets and endothelial cells in an in-vitro model of sepsis

Vitamin C and Microvascular Dysfunction in Systemic Inflammation

α1-Adrenergic Stimulation Increases Platelet Adhesion to Endothelial Cells Mediated by TRPC6

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