title: HMGB1 facilitates hypoxia-induced vWF upregulation through TLR2-MYD88-SP1 pathway.
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.
authors.affiliation: Department of Physiology, Defence Institute of Physiology and Allied Sciences, Lucknow Road, Timarpur, Delhi, India.
authors.forename: Bandana
authors.initials: B
authors.lastname: Singh
authors.affiliation: Department of Physiology, Defence Institute of Physiology and Allied Sciences, Lucknow Road, Timarpur, Delhi, India.
authors.forename: Indranil
authors.initials: I
authors.lastname: Biswas
authors.affiliation: Department of Physiology, Defence Institute of Physiology and Allied Sciences, Lucknow Road, Timarpur, Delhi, India.
authors.forename: Saumya
authors.initials: S
authors.lastname: Bhagat
authors.affiliation: Department of Physiology, Defence Institute of Physiology and Allied Sciences, Lucknow Road, Timarpur, Delhi, India.
authors.forename: Sarada
authors.initials: S
authors.lastname: Surya Kumari
authors.affiliation: Department of Physiology, Defence Institute of Physiology and Allied Sciences, Lucknow Road, Timarpur, Delhi, India. gausalk@gmail.com.
authors.forename: Gausal A
authors.initials: GA
authors.lastname: Khan
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000276:immunology* / Q000628:therapy; D019695:Glycyrrhizic Acid / Q000494:pharmacology; D024243:HMGB1 Protein / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000860:Hypoxia / Q000276:immunology* / Q000628:therapy; D007136:Immunoglobulins / Q000378:metabolism; D007333:Insulin Resistance; D051379:Mice; D058990:Molecular Targeted Therapy; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D014841:von Willebrand Factor / Q000378:metabolism*
chemical_list: D019138:Antibodies, Blocking; D024243:HMGB1 Protein; D007136:Immunoglobulins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D034741:RNA, Small Interfering; C090698:SP1 antigen; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D014841:von Willebrand Factor; D019695:Glycyrrhizic Acid
keywords: Cardiovascular diseases; HMGB1; Hypoxia; TLR2-MYD88-SP1 pathway; Transcriptional regulation