{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T20:57:06Z","timestamp":1791320226953,"version":"4.3.1"},"reference-count":49,"publisher":"American Physiological Society","issue":"6","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Lung Cellular and Molecular Physiology"],"published-print":{"date-parts":[[2012,3,15]]},"abstract":"<jats:p> Mutations in the bone morphogenetic protein (BMP) type II receptor (BMPR-II) underlie most cases of heritable pulmonary arterial hypertension (HPAH) and a significant proportion of sporadic cases. Pulmonary artery smooth muscle cells (PASMCs) from patients with pulmonary arterial hypertension (PAH) not only exhibit attenuated growth suppression by BMPs, but an abnormal mitogenic response to transforming growth factor (TGF)-\u03b21. We sought to define the mechanism underlying this loss of the antiproliferative effects of TGF-\u03b21 in BMPR-II-deficient PASMCs. The effect of TGF-\u03b21 on PASMC proliferation was characterized in three different models of BMPR-II dysfunction: 1) HPAH PASMCs, 2) Bmpr2<jats:sup>+\/\u2212<\/jats:sup> mouse PASMCs, and 3) control human PASMCs transfected with BMPR-II small interfering RNA. BMPR-II reduction consistently conferred insensitivity to growth inhibition by TGF-\u03b21. This was not associated with altered canonical TGF-\u03b21\/Smad signaling but was associated with a secreted factor. Microarray analysis revealed that the transcriptional responses to TGF-\u03b21 differed between control and HPAH PASMCs, particularly regarding genes associated with interleukins and inflammation. HPAH PASMCs exhibited enhanced IL-6 and IL-8 induction by TGF-\u03b21, an effect reversed by NF-\u03baB inhibition. Moreover, neutralizing antibodies to IL-6 or IL-8 restored the antiproliferative effect of TGF-\u03b21 in HPAH PASMCs. This study establishes that BMPR-II deficiency leads to failed growth suppression by TGF-\u03b21 in PASMCs. This effect is Smad-independent but is associated with inappropriately altered NF-\u03baB signaling and enhanced induction of IL-6 and IL-8 expression. Our study provides a rationale to test anti-interleukin therapies as an intervention to neutralize this inappropriate response and restore the antiproliferative response to TGF-\u03b21. <\/jats:p>","DOI":"10.1152\/ajplung.00309.2011","type":"journal-article","created":{"date-parts":[[2012,1,7]],"date-time":"2012-01-07T03:29:23Z","timestamp":1325906963000},"page":"L604-L615","source":"Crossref","is-referenced-by-count":113,"title":["BMP type II receptor deficiency confers resistance to growth inhibition by TGF-\u03b2 in pulmonary artery smooth muscle cells: role of proinflammatory cytokines"],"prefix":"10.1152","volume":"302","author":[{"given":"Rachel J.","family":"Davies","sequence":"first","affiliation":[{"name":"Division of Respiratory Medicine and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan M.","family":"Holmes","sequence":"additional","affiliation":[{"name":"Respiratory Disease Area, Novartis Horsham Research Centre, Horsham, West Sussex, United 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