Activated protein C, a natural anticoagulant protein, has antioxidant properties and inhibits lipid peroxidation and advanced glycation end products formation

Yamaji, Kazuyo; Wang, Yin; Liu, Yan; Abeyama, Kazuhiro; Hashiguchi, Teruto; Uchimura, Tomonori; Biswas, Kamal Krishna; Iwamoto, Hisahiko; Maruyama, Ikuro

doi:10.1016/j.thromres.2004.09.011

Cited by 42 publications

(25 citation statements)

References 29 publications

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“…An impact of aPC on ER-markers and on mitochondria, which are closely linked with ER-function, has been previously shown33–36. However, the physiological and pathophysiological relevance and the mechanism of aPC dependent regulation of ER-homeostasis remained unknown.…”

Section: Discussionmentioning

confidence: 99%

Signal integration at the PI3K-p85-XBP1 hub endows coagulation protease activated protein C with insulin-like function

Madhusudhan

Wang

Ghosh

et al. 2017

Blood

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Coagulation proteases have increasingly recognized functions beyond hemostasis and thrombosis. Disruption of activated protein C (aPC) or insulin signaling both impair function of podocytes and ultimately cause dysfunction of the glomerular filtration barrier and diabetic kidney disease (DKD). We here show that insulin and aPC converge on a common spliced-X-box binding protein-1 (sXBP1) signaling pathway to maintain endoplasmic reticulum (ER)-homeostasis. Analogous to insulin, physiological levels of aPC maintain endoplasmic reticulum (ER) proteostasis in DKD. Accordingly, genetically impaired protein C activation exacerbates maladaptive ER-response, while genetic or pharmacological restoration of aPC maintains ER-proteostasis in DKD models. Importantly, in mice with podocyte specific deficiency of insulin receptor (INSR), aPC selectively restores the activity of the cytoprotective ER-transcription factor sXBP1 by temporally targeting INSR downstream signaling intermediates, the regulatory subunits of PI3Kinase, p85α and p85β. Genome-wide mapping of condition-specific XBP1-transcriptional regulatory patterns confirmed that concordant UPR target genes are involved in maintenance of ER-proteostasis by both insulin and aPC. Thus, aPC efficiently employs disengaged insulin signaling components to re-configure ER-signaling and restore proteostasis. These results identify ER-reprogramming as a novel hormone-like function of coagulation proteases and demonstrate that targeting insulin signaling intermediates may be a feasible therapeutic approach ameliorating defective insulin signaling.

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Section: Discussionmentioning

confidence: 99%

Signal integration at the PI3K-p85-XBP1 hub endows coagulation protease activated protein C with insulin-like function

Madhusudhan

Wang

Ghosh

et al. 2017

Blood

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“…*P Ͻ 0.05 compared with nontreated aortas from the LPS group. associated with multiple cytoprotective effects including: 1) downregulation of proinflammatory gene expression (17,41); 2) antiapoptotic activity (3); 3) antioxidant properties (43), and 4) protection of the endothelial barrier function (21,35), mediated by EPCR and the effectors' receptor PAR-1 (12).…”

Section: Discussionmentioning

confidence: 99%

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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“…[13][14][15] Li et al have shown that K suppressed the cell death of oligodendrocytes depleted of reducing reagents in a culture medium.…”

Section: Vitamin K Orally Ingested Through the Diet Suppressed Lps-inmentioning

confidence: 99%

Vitamin K Suppresses Lipopolysaccharide-Induced Inflammation in the Rat

Ohsaki

Shirakawa

Hiwatashi

et al. 2006

Bioscience, Biotechnology, and Biochemistry

164

134

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Activated protein C, a natural anticoagulant protein, has antioxidant properties and inhibits lipid peroxidation and advanced glycation end products formation

Cited by 42 publications

References 29 publications

Signal integration at the PI3K-p85-XBP1 hub endows coagulation protease activated protein C with insulin-like function

Signal integration at the PI3K-p85-XBP1 hub endows coagulation protease activated protein C with insulin-like function

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

Vitamin K Suppresses Lipopolysaccharide-Induced Inflammation in the Rat

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