Nonanticoagulant Heparin Prevents Coronary Endothelial Dysfunction After Brief Ischemia-Reperfusion Injury in the Dog

Kouretas, Peter C.; Kim, Young D.; Cahill, Paul A.; Myers, Adam K.; To, Lam N.; Wang, Yining; Sitzmann, James V.; Hannan, Robert L.

doi:10.1161/01.cir.99.8.1062

Cited by 29 publications

(17 citation statements)

References 46 publications

(61 reference statements)

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“…This study also examined the regula-tion of these chemokines in atheroma-associated cells by NO, another agent implicated in the pathogenesis of atherosclerosis. Normal vascular ECs secrete NO in response to shear stress, whereas ECs overlying atherosclerotic plaques produce less NO (41). In addition to its vascular relaxing effects, NO plays important immunoregulatory functions, such as inhibiting nuclear factor-κB (NF-κB) activation.…”

Section: Discussionmentioning

confidence: 99%

“…Because IFN-γ appears to have a proatherogenic effect, we have hypothesized that the IFN-γ-inducible chemokines IP-10, Mig, and I-TAC play an important role in atherosclerosis. Moreover, we investigated whether CD40 ligand (CD154), a molecule recently implicated in atherosclerosis (38,39), and nitric oxide (NO), which has an antiatherogenic effect (40,41), would regulate IP-10, Mig, and I-TAC expression.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Differential expression of three T lymphocyte-activating CXC chemokines by human atheroma-associated cells

Mach¹,

Sauty²,

Iarossi³

et al. 1999

J. Clin. Invest.

421

262

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Differential expression of three T lymphocyte-activating CXC chemokines by human atheroma-associated cells

Mach¹,

Sauty²,

Iarossi³

et al. 1999

J. Clin. Invest.

421

262

View full text Add to dashboard Cite

“…Inhibition of L-selectin or P-selectin with mAbs or sLex-related compounds attenuates neutrophil accumulation in reperfused organ, reduces the area at risk of infarction or acute organ dysfunction, and results in better recovery. Some heparin preparations can preserve myocardial contractility after ischemia/reperfusion injury or reduce brain injury (83)(84)(85)(86). The anti-L-selectin and anti-P-selectin activity of heparin could constitute a major mechanism by which heparin derivatives may prevent reperfusion injury.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Selectin-mediated Cell Adhesion and Prevention of Acute Inflammation by Nonanticoagulant Sulfated Saccharides

Xie¹,

Rivier²,

Zakrzewicz³

et al. 2000

Journal of Biological Chemistry

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Selectins play a major role in the inflammatory reaction by initiating neutrophil attachment to activated vascular endothelium. Some heparin preparations can interact with L-and P-selectin; however, the determinants required for inhibiting selectin-mediated cell adhesion have not yet been characterized. We now report that carboxyl-reduced and sulfated heparin (prepared by chemical modifications of porcine intestinal mucosal heparin leading to the replacement of carboxylates by O-sulfate groups) and trestatin A sulfate (obtained by sulfation of trestatin A, a non-uronic pseudo-nonasaccharide extracted from Streptomyces dimorphogenes) exhibit strong anti-P-selectin and anti-L-selectin activity while lacking antithrombin-mediated anticoagulant activity. In vitro experiments revealed that both compounds inhibited P-selectin-and L-selectin-mediated cell adhesion under laminar flow conditions. Moreover, carboxyl-reduced and sulfated heparin and trestatin A sulfate were also active in vivo, as assessed by experiments showing 1) that microinfusion of trestatin A sulfate reduced by 96% leukocyte rolling along rat mesenteric postcapillary venules and 2) that both compounds inhibited (by 58 -81%) neutrophil migration into thioglycollate-inflamed peritoneum of BALB/c mice. These results indicate that nonanticoagulant sulfated saccharides targeted at P-selectin and L-selectin may have therapeutic potential in inflammatory disorders.Leukocyte migration in inflammatory lesions is a reaction that is sequentially regulated by adhesion receptors and inflammation products. Selectins play a major role in initiating neutrophil attachment to cytokine-activated endothelium. Lselectin is expressed by most circulating leukocytes; E-selectin expression is induced after several hours of endothelial cell activation by interleukin-1, tumor necrosis factor-␣, or endotoxin; P-selectin is rapidly expressed by endothelial cells or platelets exposed to thrombin or histamine (1-6).Due to different kinetics of expression, the various selectins function at different, although overlapping, phases of the inflammatory reaction. The earliest phase (Ͻ20 min) of neutrophil spontaneous rolling in rat postcapillary venules is mainly dependent on interactions between P-selectin and its major ligand P-selectin glycoprotein-1 (PSGL-1), 1 whereas L-selectin involvement is observed during a later phase (7-12). Several observations indicated that PSGL-1 is a common ligand for L-, P-, and E-selectin (13-16). This mucin-like glycoprotein is expressed by most leukocytes and interacts with L-selectin and P-selectin through a N-terminal tyrosine sulfation consensus and sialylated, fucosylated core-2 branched O-glycans (4,14,(17)(18)(19)(20)(21)(22)(23)(24). Importantly, interactions between L-selectin and PSGL-1 mediate the attachment of circulating neutrophils to neutrophils already adherent to the endothelium, a process that may increase neutrophil recruitment in inflamed tissues (25,26).Selectins share a common primary structure with a N-terminal lectin domain tha...

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“…Thrombosis leads to further endothelial dysfunction and reduced tissue perfusion. Although anticoagulants such as heparin have been shown to be protective in IRI, the mechanism of protection relates to complement inhibition, the prevention of endothelial cell dysfunction and the release of vasoactive mediators from the endothelium, rather than direct anticoagulant effects (Kouretas, Kim et al 1999). Kidney IRI was attenuated by soluble thrombomodulin treatment either before or after ischaemia.…”

Section: Coagulationmentioning

confidence: 99%

Ischaemia Reperfusion Injury in Kidney Transplantation

Rajakumar¹,

Dwyer²

2012

Organ Donation and Transplantation - Public Policy and Clinical Perspectives

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Nonanticoagulant Heparin Prevents Coronary Endothelial Dysfunction After Brief Ischemia-Reperfusion Injury in the Dog

Abstract: These results suggest that heparin preserves coronary endothelial function after brief IR injury by a mechanism independent of its anticoagulant activity and that the effect of heparin may be mediated in part by activation of the NO-cGMP pathway.

Cited by 29 publications

References 46 publications

Differential expression of three T lymphocyte-activating CXC chemokines by human atheroma-associated cells

Differential expression of three T lymphocyte-activating CXC chemokines by human atheroma-associated cells

Inhibition of Selectin-mediated Cell Adhesion and Prevention of Acute Inflammation by Nonanticoagulant Sulfated Saccharides

Ischaemia Reperfusion Injury in Kidney Transplantation

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