Changes in HDL-associated apolipoproteins relate to mortality in human sepsis and correlate to monocyte and platelet activation

Barlage, Stefan; Gnewuch, Carsten; Liebisch, Gerhard; Wolf, Zsuzsanna; Audebert, Franz-Xaver; Glück, Thomas; Fröhlich, D.; Krämer, Bernhard K.; Rothe, Gregor; Schmitz, Gerd

doi:10.1007/s00134-009-1609-y

Cited by 132 publications

(134 citation statements)

References 34 publications

Supporting

Mentioning

121

Contrasting

Unclassified

Order By: Relevance

“…Consistent with this notion, clinical remission of TTP after plasma exchange has been observed in the face of persistent ADAMTS13 deficiency and elevated titers of inhibitory antibodies. 36 In addition to high total active VWF, low HDL and ApoA-I levels have also been described in sepsis, 37 malaria, 38 and sickle cell disease, 39,40 suggesting that higher ApoA-I concentrations may be protective of microvascular occlusion. Consistent with this suggestion, increased mortality associated with polymicrobial sepsis was observed in ApoA-Ideficient mice.…”

Section: Discussionmentioning

confidence: 99%

High-density lipoprotein modulates thrombosis by preventing von Willebrand factor self-association and subsequent platelet adhesion

Chung

Chen

Ling

et al. 2016

Blood

View full text Add to dashboard Cite

• High-density lipoprotein and its major apolipoprotein ApoA-I prevent von Willebrand factor self-association. • Targeting von Willebrand factor self-association could be a new approach to treating thrombotic disorders.The ability of von Willebrand factor (VWF) to initiate platelet adhesion depends on the number of monomers in individual VWF multimers and on the self-association of individual VWF multimers into larger structures. VWF self-association is accelerated by shear stress. We observed that VWF self-association occurs during adsorption of VWF onto surfaces, assembly of secreted VWF into hyperadhesive VWF strings on the endothelial surface, and incorporation of fluid-phase VWF into VWF fibers. VWF adsorption under static conditions increased with increased VWF purity and was prevented by a component of plasma. We identified that component as high-density lipoprotein (HDL) and its major apolipoprotein ApoA-I. HDL and ApoA-I also prevented VWF on the endothelium from self-associating into longer strands and inhibited the attachment of fluid-phase VWF onto vessel wall strands. Platelet adhesion to VWF fibers was reduced in proportion to the reduction in selfassociated VWF. In a mouse model of thrombotic microangiopathy, HDL also largely prevented the thrombocytopenia induced by injection of high doses of human VWF. Finally, a potential role for ApoA-I in microvascular occlusion associated with thrombotic thrombocytopenic purpura and sepsis was revealed by the inverse relationship between the concentration of ApoA-I and that of hyperadhesive VWF. These results suggest that interference with VWF self-association would be a new approach to treating thrombotic disorders. are characterized by systemic endothelial activation and microvascular occlusion. In recent studies, von Willebrand factor (VWF) secreted from the endothelium as a result of systemic endothelial activation has been shown to contribute to microvascular dysfunction and occlusion. A portion of the newly secreted VWF remains attached to the endothelial surface, from which it is normally removed through cleavage by the plasma metalloprotease ADAMTS13. 6 However, when ADAMTS13 is inhibited, as during episodes of TTP, or when VWF removal is delayed, as in conditions of intense inflammation such as sepsis and malaria, 7 the secreted VWF self-associates into long, thick strands that bind platelets to form occlusive thrombi in the small blood vessels. 6 VWF synthesis is a complex process. VWF homodimers first form in the endoplasmic reticulum through disulfide bonds involving cysteine residues near the VWF carboxyl terminus. In the Golgi apparatus, these dimers are linked together into chains through disulfide bonds at the amino termini, producing a ladder of multimeric molecules, each differing from the next largest by the molecular mass of a VWF dimer. The largest multimers found in blood can be enormous, reaching a molecular mass of more than 20 million Da. These gargantuan molecules can form even larger structures by associating with other VWF multime...

show abstract

Section: Discussionmentioning

confidence: 99%

High-density lipoprotein modulates thrombosis by preventing von Willebrand factor self-association and subsequent platelet adhesion

Chung

Chen

Ling

et al. 2016

Blood

View full text Add to dashboard Cite

show abstract

“…Viral respiratory infection or sepsis was not clinically evident at time of sample collection from our subjects. 41 No type 1 diabetes mellitus or advanced renal dysfunction (less than chronic kidney disease stage 2) characterized our PAH subjects. 21,42 In addition, although our bioassay of monocyte chemotaxis has been extensively validated and standardized in our prior investigations using cultured aortic ECs, we cannot discount the inherent differences between aortic and pulmonary arterial endothelium, which may have influenced our findings.…”

Section: Discussionmentioning

confidence: 99%

Proinflammatory High‐Density Lipoprotein Results from Oxidized Lipid Mediators in the Pathogenesis of Both Idiopathic and Associated Types of Pulmonary Arterial Hypertension

et al. 2015

View full text Add to dashboard Cite

Pulmonary arterial hypertension (PAH) is characterized by abnormal elaboration of vasoactive peptides, endothelial cell dysfunction, vascular remodeling, and inflammation, which collectively contribute to its pathogenesis. We investigated the potential for highdensity lipoprotein (HDL) dysfunction (i.e., proinflammatory effects) and abnormal plasma eicosanoid levels to contribute to the pathobiology of PAH and assessed ex vivo the effect of treatment with apolipoprotein A-I mimetic peptide 4F on the observed HDL dysfunction. We determined the "inflammatory indices" HII and LII for HDL and low-density lipoprotein (LDL), respectively, in subjects with idiopathic PAH (IPAH) and associated PAH (APAH) by an in vitro monocyte chemotaxis assay. The 4F was added ex vivo, and repeat LII and HII values were obtained versus a sham treatment. We further determined eicosanoid levels in plasma and HDL fractions from patients with IPAH and APAH relative to controls. The LIIs were significantly higher for IPAH and APAH patients than for controls. Incubation of plasma with 4F before isolation of LDL and HDL significantly reduced the LII values, compared with sham-treated LDL, for IPAH and APAH. The increased LII values reflected increased states of LDL oxidation and thereby increased proinflammatory effects in both cohorts. The HIIs for both PAH cohorts reflected a "dysfunctional HDL phenotype," that is, proinflammatory HDL effects. In contrast to "normal HDL function," the determined HIIs were significantly increased for the IPAH and APAH cohorts. Ex vivo 4F treatment significantly improved the HDL function versus the sham treatment. Although there was a significant "salutary effect" of 4F treatment, this did not entirely normalize the HII. Significantly increased levels for both IPAH and APAH versus controls were evident for the eicosanoids 9-HODE, 13-HODE, 5-HETE, 12-HETE, and 15-HETE, while no statistical differences were evident for comparisons of IPAH and APAH for the determined plasma eicosanoid levels in the HDL fractions. Our study has further implicated the putative role of "oxidant stress" and inflammation in the pathobiology of PAH. Our data suggest the influences on the "dysfunctional HDL phenotype" of increased oxidized fatty acids, which are paradoxically proinflammatory. We speculate that therapies that target either the "inflammatory milieu" or the "dysfunctional HDL phenotype," such as apoA-I mimetic peptides, may be valuable avenues of further research in pulmonary vascular diseases.Keywords: pulmonary arterial hypertension, low-density lipoprotein, high-density lipoprotein, inflammatory index, hydroxyeicosatetraenoic acids, hydroxyoctadecadienoic acids, pulmonary arterial endothelial cells, pulmonary arterial smooth muscle cells.

show abstract

“…During inflammation, the metabolism of HDL is markedly affected [19], leading to decreasing levels of HDL. Low levels of HDL have been shown to be related to increased mortality in sepsis [20,21].…”

Section: Introductionmentioning

confidence: 99%

Propofol and perioperative inflammation-the Intralipid® solvent may play a role

Bandschapp¹,

Chenaud²,

Inan³

et al. 2015

Glob Anesth Perioper Med

View full text Add to dashboard Cite

The inflammatory properties of propofol are still debated. Apolipoprotein A-I is involved in the inflammation. We sought to determine how propofol or its solvent Intralipid® modulate Apolipoprotein A-I and the inflammatory response after surgical stress. Patients undergoing laparoscopic inguinal hernia repair were allocated to anesthesia with propofol (n=25), isoflurane alone (n=27) or in combination with Intralipid® (n=27). Apolipoprotein A-I and inflammation were assessed before, during and after surgery. Following a decrease in all groups, Apolipoprotein A-I levels tended to recover significantly earlier when propofol or Intralipid® were given (p<0.05). Cortisol increased in the control group whereas it remained at baseline levels when lipids were given. In this study the administration of lipids, i.e. propofol or its solvent Intralipid®, in the perioperative setting was associated with a more pronounced yet rapidly recovering acute phase reaction.

show abstract

Changes in HDL-associated apolipoproteins relate to mortality in human sepsis and correlate to monocyte and platelet activation

Cited by 132 publications

References 34 publications

High-density lipoprotein modulates thrombosis by preventing von Willebrand factor self-association and subsequent platelet adhesion

High-density lipoprotein modulates thrombosis by preventing von Willebrand factor self-association and subsequent platelet adhesion

Proinflammatory High‐Density Lipoprotein Results from Oxidized Lipid Mediators in the Pathogenesis of Both Idiopathic and Associated Types of Pulmonary Arterial Hypertension

Propofol and perioperative inflammation-the Intralipid® solvent may play a role

Contact Info

Product

Resources

About