Activated protein C improves lipopolysaccharide-induced cardiovascular dysfunction by decreasing tissular inflammation and oxidative stress*

Sennoun, N.; Meziani, Ferhat; Dessebe, Olivier; Cattan, Valérie; Collin, Solène; Montemont, Chantal; Gibot, Sébastien; Asfar, Pierre; Andriantsitohaina, Ramaroson; Régnault, V.; Slama, Michel; Lecompte, Thomas; Lacolley, Patrick; Lévy, Bruno

doi:10.1097/ccm.0b013e318192fe4f

Cited by 43 publications

(18 citation statements)

References 49 publications

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“…To our knowledge, this is the first study reporting new vascular insight on the benefits of the ex vivo nonanticoagulant effect of rhAPC on endothelial dysfunction induced by LPS, which involves several related cellular mechanisms. As previously reported, rhAPC likely contributes in limiting the process of refractory vasoplegia in patients with septic shock (28) as well as in endotoxemic rats (30) . Hence, rhAPC is able to blunt iNOS expression and probably subsequent NO production, resulting in an improvement in PE curve-dose contractility.…”

Section: Discussionmentioning

confidence: 61%

“…Recent animal (13,30,40) and human (28) studies have suggested that rhAPC may improve hemodynamic and vascular reactivity to catecholamines during septic states. However, much of our current knowledge concerning rhAPC vascular activity is still much debated, especially with respect to its nonanticoagulant properties.…”

Section: Discussionmentioning

confidence: 99%

“…Aortic rings (2-3 mm) and second-order SMA were emptied of blood and randomly incubated for 12 h in RPMI/medium 199 1:1 (blood free) supplemented with 10% bovine fetal serum with (LPS ϩ rhAPC group) or without (LPS group) rhAPC (drotecogin ␣ activated, Xigris; Lilly, Indianapolis, IN) (50 ng/ml). This dosage corresponds to human plasma therapeutic concentration ranges, as well as to the concentration used in our previous study (30).…”

Section: Animals and Protocolsmentioning

confidence: 99%

“…In a previous experimental study (30), we reported that recombinant human APC (rhAPC) improved cardiovascular function 1) by modulating the endotoxin-induced proinflammatory/prooxydant state, 2) by decreasing cell adhesion, and 3) by favoring stabilization of the extracellular matrix. These results may well be related to APC anticoagulant and/or nonanticoagulant activities observed in experimental endotoxemia (16,19).…”

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confidence: 99%

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Recombinant human activated protein C improves endotoxemia-induced endothelial dysfunction: a blood-free model in isolated mouse arteries

Sennoun¹,

Baron-Menguy²,

Burban³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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Recombinant human activated protein C (rhAPC) is one of the treatment panels for improving vascular dysfunction in septic patients. In a previous study, we reported that rhAPC treatment in rat endotoxemia improved vascular reactivity, although the mechanisms involved are still under debate. In the present study, we hypothesized that rhAPC may improve arterial dysfunction through its nonanticoagulant properties. Ten hours after injection of LPS in mice (50 mg/kg ip), aortic rings and mesenteric arteries were isolated and incubated with or without rhAPC for 12 h. Aortic rings were mounted in a myograph, after which arterial contractility and endothelium-dependent relaxation were measured in the presence or absence of nitric oxide synthase or cyclooxygenase inhibitors. Flow (shear stress)-mediated dilation with or without the above inhibitors was also measured in mesenteric resistance arteries. Protein expression was assessed by Western blotting. Lipopolysaccharide (LPS) reduced aortic contractility to KCl and phenylephrine as well as dilation to acetylcholine. LPS also reduced flow-mediated dilation in mesenteric arteries. In rhAPC-treated aorta and mesenteric arteries, contractility and endothelial responsiveness to vasodilator drug and shear stress were improved. rhAPC treatment also improved LPS-induced endothelial dysfunction; this effect was associated with an increase in the phosphorylated form of endothelial nitric oxide synthase and protein kinase B as well as cyclooxygenase vasodilatory pathways, thus suggesting that these pathways, together with the decrease in nuclear factor-κB activation and inducible nitric oxide synthase expression in the vascular wall, are implicated in the endothelial effect of rhAPC. In conclusion, ex vivo application of rhAPC improves arterial contractility and endothelial dysfunction resulting from endotoxemia in mice. This finding provides important insights into the mechanism underlying rhAPC-induced improvements on arterial dysfunction during septic shock.

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Section: Discussionmentioning

confidence: 61%

Section: Discussionmentioning

confidence: 99%

Section: Animals and Protocolsmentioning

confidence: 99%

mentioning

confidence: 99%

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Recombinant human activated protein C improves endotoxemia-induced endothelial dysfunction: a blood-free model in isolated mouse arteries

Sennoun¹,

Baron-Menguy²,

Burban³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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“…Indeed, data from the PROWESS study demonstrated that the use of APC was associated with a quicker reduction in cardiovascular failure. Post-PROWESS investigative areas have been associated with a myriad of cellular studies [70] demonstrating that APC, through reactions mediated by the endothelial protein C receptor (EPCR) [71] and the effector receptor (protease activated receptor-1), acts directly on cells to exert multiple cytoprotective effects including: (a) downregulation of proinflammatory gene expression [72]; (b) anti-apoptotic activity [73]; (c) antioxidant properties; and (d) protection of endothelial barrier function [74]. Recent animal [75] and human [76] data have suggested that APC may improve both vascular and myocardial dysfunction and vascular reactivity to catecholamines during endotoxin and/or septic challenges.…”

Section: Activated Protein Cmentioning

confidence: 99%

Vascular hyporesponsiveness to vasopressors in septic shock: from bench to bedside

Lévy

Collin

Sennoun

et al. 2012

Applied Physiology in Intensive Care Medicine 2

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Vascular hyporesponsiveness to vasopressors in septic shock: from bench to bedside Abstract Purpose: To delineate some of the characteristics of septic vascular hypotension, to assess the most commonly cited and reported underlying mechanisms of vascular hyporesponsiveness to vasoconstrictors in sepsis, and to briefly outline current therapeutic strategies and possible future approaches. Methods: Source data were obtained from a PubMed search of the medical literature with the following MeSH terms: Muscle, smooth, vascular/ physiopathology; hypotension/etiology; shock/physiopathology; vasodilation/physiology; shock/therapy; vasoconstrictor agents. Results: Nitric oxide (NO) and peroxynitrite are crucial components implicated in vasoplegia and vascular hyporeactivity. Vascular ATP-sensitive and calcium-activated potassium channels are activated during shock and participate in hypotension. In addition, shock state is characterized by inappropriately low plasma glucocorticoid and vasopressin concentrations, a dysfunction and desensitization of alpha-receptors, and an inactivation of catecholamines by oxidation. Numerous other mechanisms have been individualized in animal models, the great majority of which involve NO: MEK1/2-ERK1/2 pathway, H 2 S, hyperglycemia, and cytoskeleton dysregulation associated with decreased actin expression. Conclusions: Many therapeutic approaches have proven their efficiency in animal models, especially therapies directed against one particular compound, but have otherwise failed when used in human shock. Nevertheless, high doses of catecholamines, vasopressin and terlipressin, hydrocortisone, activated protein C, and non-specific shock treatment have demonstrated a partial efficiency in reversing sepsis-induced hypotension.

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Repositioning of the antipsychotic drug TFP for sepsis treatment

Park

Lee

et al. 2019

J Mol Med

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Sepsis is a disease responsible for the death of almost all critical patients. Once infected by virus or bacteria, patients can die due to systemic inflammation within a short period of time. Cytokine storm plays an essential role in causing organ dysfunction and septic shock. Thus, inhibition of cytokine secretion is considered very important in sepsis therapy. In this study, we found that TFP, an antipsychotic drug mainly used to treat schizophrenia by suppressing dopamine secretion, inhibited cytokine release from activated immune cells both in vitro and in vivo. Trifluoperazine (TFP) decreased the levels of pro-inflammatory cytokines without altering their transcription level. In LPS-induced endotoxemia and cecal content injection (CCI) models, TFP intraperitoneal administration improved survival rate. Thus, TFP was considered to inhibit the secretion of proteins through a mechanism similar to that of W7, a calmodulin inhibitor. Finally, we confirmed that TFP treatment relieved organ damage by estimating the concentrations of aspartate transaminase (AST), alanine transaminase (ALT), and blood urea nitrogen (BUN) in the serum. Our findings were regarded as a new discovery of the function of TFP in treating sepsis patients. Key messages • TFP inhibits LPS-induced activation of DCs by suppressing pro-inflammatory cytokine. • Treatment of TFP increases survival of LPS-induced endotoxemia and CCI sepsis models. • TFP exerted a protective effect against tissue or organ damage in animal models. Electronic supplementary material The online version of this article (10.1007/s00109-019-01762-4) contains supplementary material, which is available to authorized users.

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Activated protein C improves lipopolysaccharide-induced cardiovascular dysfunction by decreasing tissular inflammation and oxidative stress*

Abstract: These data suggest that APC improves cardiovascular function: 1) by modulating the endotoxin induced-proinflammatory/prooxidant state, 2) by decreasing endothelial/leukocyte interaction and 3) by favoring stabilization of the extracellular matrix.

Cited by 43 publications

References 49 publications

Recombinant human activated protein C improves endotoxemia-induced endothelial dysfunction: a blood-free model in isolated mouse arteries

Recombinant human activated protein C improves endotoxemia-induced endothelial dysfunction: a blood-free model in isolated mouse arteries

Vascular hyporesponsiveness to vasopressors in septic shock: from bench to bedside

Repositioning of the antipsychotic drug TFP for sepsis treatment

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