TY - JOUR
T1 - Bone morphogenetic protein receptor type II deficiency and increased inflammatory cytokine production
T2 - A gateway to pulmonary arterial hypertension
AU - Soon, Elaine
AU - Crosby, Alexi
AU - Southwood, Mark
AU - Yang, Peiran
AU - Tajsic, Tamara
AU - Toshner, Mark
AU - Appleby, Sarah
AU - Shanahan, Catherine M.
AU - Bloch, Kenneth D.
AU - Pepke-Zaba, Joanna
AU - Upton, Paul
AU - Morrell, Nicholas W.
PY - 2015/10/1
Y1 - 2015/10/1
N2 - Rationale: Mutations in bonemorphogenetic protein receptor type II (BMPR-II) underlie most cases of heritable pulmonary arterial hypertension (PAH). However, disease penetrance is only 20-30%, suggesting a requirement for additional triggers. Inflammation is emerging as a key disease-related factor in PAH, but to date there is no clear mechanism linking BMPR-II deficiency and inflammation. Objectives: To establish a direct link between BMPR-II deficiency, a consequentially heightened inflammatory response, and development of PAH. Methods: We used pulmonary artery smooth muscle cells from Bmpr2+/- mice and patients with BMPR2 mutations and compared them with wild-type controls. For the in vivo model, we used mice heterozygous for a null allele in Bmpr2 (Bmpr2+/-) and wild-type littermates. Measurements and Main Results: Acute exposure to LPS increased lung and circulating IL-6 and KC (IL-8 analog) levels in Bmpr2+/- mice to a greater extent than in wild-type controls. Similarly, pulmonary artery smooth muscle cells from Bmpr2+/- mice and patients with BMPR2 mutations produced higher levels of IL-6 and KC/IL-8 after lipopolysaccharide stimulation compared with controls. BMPR-II deficiency in mouse and human pulmonary artery smooth muscle cells was associated with increased phospho-STAT3 and loss of extracellular superoxide dismutase. Chronic lipopolysaccharide administration caused pulmonary hypertension in Bmpr2+/- mice but not in wild-type littermates. Coadministration of tempol, a superoxide dismutase mimetic, ameliorated the exaggerated inflammatory response and prevented development of PAH. Conclusions: This study demonstrates that BMPR-II deficiency promotes an exaggerated inflammatory response in vitro and in vivo, which can instigate development of pulmonary hypertension.
AB - Rationale: Mutations in bonemorphogenetic protein receptor type II (BMPR-II) underlie most cases of heritable pulmonary arterial hypertension (PAH). However, disease penetrance is only 20-30%, suggesting a requirement for additional triggers. Inflammation is emerging as a key disease-related factor in PAH, but to date there is no clear mechanism linking BMPR-II deficiency and inflammation. Objectives: To establish a direct link between BMPR-II deficiency, a consequentially heightened inflammatory response, and development of PAH. Methods: We used pulmonary artery smooth muscle cells from Bmpr2+/- mice and patients with BMPR2 mutations and compared them with wild-type controls. For the in vivo model, we used mice heterozygous for a null allele in Bmpr2 (Bmpr2+/-) and wild-type littermates. Measurements and Main Results: Acute exposure to LPS increased lung and circulating IL-6 and KC (IL-8 analog) levels in Bmpr2+/- mice to a greater extent than in wild-type controls. Similarly, pulmonary artery smooth muscle cells from Bmpr2+/- mice and patients with BMPR2 mutations produced higher levels of IL-6 and KC/IL-8 after lipopolysaccharide stimulation compared with controls. BMPR-II deficiency in mouse and human pulmonary artery smooth muscle cells was associated with increased phospho-STAT3 and loss of extracellular superoxide dismutase. Chronic lipopolysaccharide administration caused pulmonary hypertension in Bmpr2+/- mice but not in wild-type littermates. Coadministration of tempol, a superoxide dismutase mimetic, ameliorated the exaggerated inflammatory response and prevented development of PAH. Conclusions: This study demonstrates that BMPR-II deficiency promotes an exaggerated inflammatory response in vitro and in vivo, which can instigate development of pulmonary hypertension.
KW - Bone morphogenetic protein receptor type II
KW - Cytokine
KW - Inflammation
KW - Lipopolysaccharide
KW - Pulmonary hypertension
UR - http://www.scopus.com/inward/record.url?scp=84943266030&partnerID=8YFLogxK
U2 - 10.1164/rccm.201408-1509OC
DO - 10.1164/rccm.201408-1509OC
M3 - Article
C2 - 26073741
AN - SCOPUS:84943266030
SN - 1073-449X
VL - 192
SP - 859
EP - 872
JO - American Journal of Respiratory and Critical Care Medicine
JF - American Journal of Respiratory and Critical Care Medicine
IS - 7
ER -
