Hyaluronic acid binding protein 2 Is a novel regulator of vascular integrity

Nurbek Mambetsariev, Tamara Mirzapoiazova, Bolot Mambetsariev, Saad Sammani, Frances E. Lennon, Joe GN Garcia, Patrick A. Singleton

Research output: Contribution to journalArticle

40 Scopus citations

Abstract

Objective-The disruption of the endothelial cell barrier is a critical feature of inflammation and an important contributing factor to acute lung injury (ALI), an inflammatory condition that is a major cause of morbidity and mortality in critically ill patients. We evaluated the role of the extracellular serine protease, hyaluronic acid binding protein 2 (HABP2), in vascular barrier regulation. Methods and Results-By using immunoblot and immunohistochemical analysis, we observed that lipopolysaccharide (LPS) induces HABP2 expression in murine lung endothelium in vivo and in human pulmonary microvascular endothelial cells (ECs) in vitro. High-molecular-weight hyaluronan (HMW-HA, approximately 1×10 Da) decreased HABP2 protein expression in human pulmonary microvascular ECs and decreased purified HABP2 enzymatic activity, whereas low-molecular-weight HA (LMW-HA, approximately 2500 Da) increased these activities. The effects of LMW-HA, but not HMW-HA, on HABP2 activity were inhibited with a peptide of the polyanion-binding domain of HABP2. Silencing (small interfering RNA) HABP2 expression augmented HMW-HA-induced EC barrier enhancement and inhibited LPS and LMW-HA-mediated EC barrier disruption, results that were reversed with overexpression of HABP2. Silencing protease-activated receptor 1 and 3, RhoA, or Rho kinase expression attenuated LPS-, LMW-HA-, and HABP2-mediated EC barrier disruption. By using murine models of acute lung injury, we observed that LPS-and ventilator-induced pulmonary vascular hyperpermeability was significantly reduced with vascular silencing (small interfering RNA) of HABP2. Conclusion-HABP2 negatively regulates vascular integrity via activation of protease-activated receptor/RhoA/Rho kinase signaling and represents a potentially useful therapeutic target for syndromes of increased vascular permeability.

Original languageEnglish (US)
Pages (from-to)483-490
Number of pages8
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume30
Issue number3
DOIs
Publication statusPublished - Mar 2010
Externally publishedYes

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Keywords

  • Endothelial barrier function
  • HABP2
  • Hyaluronan
  • Protease-activated receptor
  • Vascular permeability

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Mambetsariev, N., Mirzapoiazova, T., Mambetsariev, B., Sammani, S., Lennon, F. E., Garcia, J. GN., & Singleton, P. A. (2010). Hyaluronic acid binding protein 2 Is a novel regulator of vascular integrity. Arteriosclerosis, Thrombosis, and Vascular Biology, 30(3), 483-490. https://doi.org/10.1161/ATVBAHA.109.200451