LRP1-Dependent BMPER Signaling Regulates Lipopolysaccharide-Induced Vascular Inflammation

Arterioscler Thromb Vasc Biol. 2017 Aug;37(8):1524-1535. doi: 10.1161/ATVBAHA.117.309521. Epub 2017 Jun 8.


Objective: Bacterial endotoxin (lipopolysaccharide)-mediated sepsis involves dysregulated systemic inflammation, which injures the lung and other organs, often fatally. Vascular endothelial cells act as both targets and mediators of lipopolysaccharide-induced inflammatory responses. Dysfunction of endothelium results in increases of proinflammatory cytokine production and permeability leakage. BMPER (bone morphogenetic protein-binding endothelial regulator), an extracellular modulator of bone morphogenetic protein signaling, has been identified as a vital component in chronic endothelial inflammatory responses and atherosclerosis. However, it is unclear whether BMPER also regulates inflammatory response in an acute setting such as sepsis. To address this question, we investigated the role of BMPER during lipopolysaccharide-induced acute lung injury.

Approach and results: Mice missing 1 allele of BMPER (BMPER+/- mice used in the place of BMPER-/- mice that die at birth) were used for lipopolysaccharide challenge. Lipopolysaccharide-induced pulmonary inflammation and injury was reduced in BMPER+/- mice as shown by several measures, including survival rate, infiltration of inflammatory cells, edema, and production of proinflammatory cytokines. Mechanistically, we have demonstrated that BMPER is required and sufficient for the activation of nuclear factor of activated T cells c1. This BMPER-induced nuclear factor of activated T cells activation is coordinated by multiple signaling pathways, including bone morphogenetic protein-independent low-density lipoprotein receptor-related protein 1-extracellular signal-regulated kinase activation, calcineurin signaling, and low-density lipoprotein receptor-related protein 1β-mediated nuclear factor 45 nuclear export in response to BMPER treatment.

Conclusions: We conclude that BMPER plays a pivotal role in pulmonary inflammatory response, which provides new therapeutic options against sepsis shock. The new signaling pathway initiated by BMPER/low-density lipoprotein receptor-related protein 1 axis broadens our understanding about BMPER's role in vascular homeostasis.

Keywords: atherosclerosis; bone morphogenetic proteins; endothelial cells; inflammation; lipopolysaccharides.

MeSH terms

  • Acute Lung Injury / chemically induced
  • Acute Lung Injury / genetics
  • Acute Lung Injury / metabolism*
  • Acute Lung Injury / pathology
  • Animals
  • Apoptosis
  • Capillary Permeability
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cells, Cultured
  • Cytokines / metabolism
  • Disease Models, Animal
  • Endothelial Cells / metabolism*
  • Endothelial Cells / pathology
  • Endotoxins*
  • Genetic Predisposition to Disease
  • Haploinsufficiency
  • Inflammation Mediators / metabolism
  • Low Density Lipoprotein Receptor-Related Protein-1
  • Lung / blood supply*
  • Lung / metabolism
  • Lung / pathology
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NFATC Transcription Factors / metabolism
  • Nuclear Factor 45 Protein / metabolism
  • Phenotype
  • Pneumonia / chemically induced
  • Pneumonia / genetics
  • Pneumonia / metabolism*
  • Pneumonia / pathology
  • RNA Interference
  • Receptors, LDL / genetics
  • Receptors, LDL / metabolism*
  • Signal Transduction*
  • Time Factors
  • Transfection
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*


  • Carrier Proteins
  • Cytokines
  • Endotoxins
  • Ilf2 protein, mouse
  • Inflammation Mediators
  • Low Density Lipoprotein Receptor-Related Protein-1
  • Lrp1 protein, mouse
  • NFATC Transcription Factors
  • Nfatc1 protein, mouse
  • Nuclear Factor 45 Protein
  • Receptors, LDL
  • Tumor Suppressor Proteins
  • crossveinless 2 protein, mouse
  • endotoxin, Escherichia coli