Journal Article

Bone Morphogenetic Protein Receptor Type II Deficiency and Increased Inflammatory Cytokine Production. A Gateway to Pulmonary Arterial Hypertension

Yang, Peiran, Toshner, Mark, Upton, Paul, Shanahan, Catherine M., Pepke-Zaba, Joanna, Morrell, Nicholas W., Appleby, Sarah, Tajsic, Tamara, Bloch, Kenneth D., Southwood, Mark, Soon, Elaine, Crosby, Alexi

2015

Overview

Mutations in bone morphogenetic 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. To establish a direct link between BMPR-II deficiency, a consequentially heightened inflammatory response, and development of PAH. 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. 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. This study demonstrates that BMPR-II deficiency promotes an exaggerated inflammatory response in vitro and in vivo, which can instigate development of pulmonary hypertension.

• Publisher: Oxford University Press,American Thoracic Society
• Subject: Animals / Antioxidants - therapeutic use / Bone Morphogenetic Protein Receptors, Type II - deficiency / Bone Morphogenetic Protein Receptors, Type II - metabolism / Cyclic N-Oxides - therapeutic use / Cytokines - biosynthesis / Fenoterol / Genetic Predisposition to Disease / Humans / Hypertension, Pulmonary - genetics / Hypertension, Pulmonary - physiopathology / Immunohistochemistry / Mice, Inbred Strains / Original / Spin Labels / Superoxide Dismutase - physiology