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2020 ; 84
(ä): 102459
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Hypoxia induced up-regulation of tissue factor is mediated through extracellular
RNA activated Toll-like receptor 3-activated protein 1 signalling
#MMPMID32559654
Bhagat S
; Biswas I
; Ahmed R
; Khan GA
Blood Cells Mol Dis
2020[Sep]; 84
(ä): 102459
PMID32559654
show ga
Sterile Inflammation (SI), a condition where damage associated molecular patterns
(DAMPs) released from dying cells, leads to TLR (Toll-like receptor) activation
and triggers hypoxemia in circulation leading to venous thrombosis (VT) through
tissue factor (TF) activation, but its importance under acute hypoxia (AH)
remains unexplored. Thus, we hypothesized that eRNA released from dying cells
under AH activates TF via the TLR3-ERK1/2-AP1 pathway, leading to VT. Animals
were exposed to stimulate hypoxia for 0-24 h at standard temperature and
humidity. RNaseA and DNase1 were injected immediately before exposure. TLR3 gene
silencing was performed through in vivo injection of TLR3 siRNA. 80 ?g/kg BW of
isolated eRNA and eDNA were injected 6 h prior to sacrifice. Antigens of TF
pathway were determined by ELISA and TF activity by a chromogenic assay. AH
exposure significantly induced release of SI markers i.e. eRNA, eDNA, HMGB1 and
upregulated TLR3, ERK1/2 (Extracellular signal-regulated kinases), AP1 (Activator
Protein-1) and TF, whereas RNaseA pre-treatment diminished the effect of AH, thus
inhibiting TF expression as well as activity during AH. Hence, we propose a
possible mechanism of AH-induced TF activation and thrombosis where RNaseA can
become the novel focal point in ameliorating therapy for AH induced thrombosis.