High-mobility group box-1 induces vascular remodelling processes via c-Jun activation.
Extracellular high-mobility group box-1 (HMGB1) acts as a signalling molecule during inflammation, cell differentiation and angiogenesis. Increased abundance of HMGB1 is associated with several pathological disorders such as cancer, asthma and chronic obstructive pulmonary disease (COPD). In this study, we investigated the relevance of HMGB1 in the pathological remodelling present in patients with idiopathic pulmonary arterial hypertension (IPAH) and pulmonary hypertension (PH) associated with COPD. Remodelled vessels present in COPD with PH and IPAH lung samples were often surrounded by HMGB1-positive cells. Increased HMGB1 serum levels were detected in both patient populations compared to control samples. The effects of physiological HMGB1 concentrations were then examined on cellular responses in vitro. HMGB1 enhanced proliferation of pulmonary arterial smooth muscle cells (PASMC) and primary human arterial endothelial cells (PAEC). HMGB1 stimulated p38, extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) phosphorylation. Furthermore, activation of the downstream AP-1 complex proteins c-Fos and c-Jun was observed. Silencing of c-Jun ablated the HMGB1-induced proliferation in PASMC. Thus, an inflammatory component such as HMGB1 can contribute to PASMC and PAEC proliferation and therefore potentially to vascular remodelling and PH pathogenesis.
Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria.
Diana
D
Zabini
Slaven
S
Crnkovic
Hui
H
Xu
Maria
M
Tscherner
Bahil
B
Ghanim
Walter
W
Klepetko
Andrea
A
Olschewski
Grazyna
G
Kwapiszewska
Leigh M
LM
Marsh
D000368:Aged; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D065627:Familial Primary Pulmonary Hypertension / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005260:Female; D024243:HMGB1 Protein / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D011651:Pulmonary Artery / Q000166:cytology; D034622:RNA Interference; D000067759:Receptor for Advanced Glycation End Products / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism; D066253:Vascular Remodeling / Q000187:drug effects / Q000235:genetics / Q000502:physiology*
C000593871:AGER protein, human; D024243:HMGB1 Protein; D000067759:Receptor for Advanced Glycation End Products; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D048031:JNK Mitogen-Activated Protein Kinases
HMGB1; alarmins; inflammation; proliferation; pulmonary hypertension