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European journal of immunology

HMGB1 facilitates hypoxia-induced vWF upregulation through TLR2-MYD88-SP1 pathway.


PMID 27480067

Abstract

Increased plasma level of von Willebrand Factor (vWF) is associated with major cardiovascular diseases. We previously reported that multimeric vWF binds to NO synthase and inhibits insulin-induced production of NO, thus promoting insulin resistance during acute hypoxia (AH). However, the transcriptional regulation of vWF during AH is not clearly understood. Here, we investigated the mechanisms underlying the upregulation of vwf in mice. AH significantly upregulates the tlr2, tlr3, myd88, and vwf expression and phosphorylation of specificity protein 1 (SP1). Furthermore, AH significantly upregulates high mobility group box-1 (HMGB1) in a time-dependent manner. Moreover, a TLR2 agonist upregulates vWF but a TLR3 agonist does not. Pretreatment with an HMGB1 inhibitor, TLR2-immunoneutralizing antibody, or SP1 inhibitor significantly inhibits vWF expression. Furthermore, Tlr2 silencing completely inhibited MYD88, vWF expression, and SP1 phosphorylation. However, pretreatment with glycyrrhizic acid or silencing of Tlr2 completely blocks binding of Sp1 to the Vwf promoter, thus inhibiting its expression, and enhances insulin resistance during AH. Patients with type 2 diabetes mellitus also showed significantly elevated levels of HMGB1, TLR2, SP1, and vWF, thereby supporting the results of the murine model of AH. Taken together, HMGB1 upregulates vWF in vivo through the TLR2-MYD88-SP1 pathway in mice.