| First Author | Davies RJ | Year | 2012 |
| Journal | Am J Physiol Lung Cell Mol Physiol | Volume | 302 |
| Issue | 6 | Pages | L604-15 |
| PubMed ID | 22227206 | Mgi Jnum | J:183433 |
| Mgi Id | MGI:5318660 | Doi | 10.1152/ajplung.00309.2011 |
| Citation | Davies RJ, et al. (2012) BMP type II receptor deficiency confers resistance to growth inhibition by TGF-beta in pulmonary artery smooth muscle cells: role of proinflammatory cytokines. Am J Physiol Lung Cell Mol Physiol 302(6):L604-15 |
| abstractText | 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)-beta1. We sought to define the mechanism underlying this loss of the antiproliferative effects of TGF-beta1 in BMPR-II-deficient PASMCs. The effect of TGF-beta1 on PASMC proliferation was characterized in three different models of BMPR-II dysfunction: 1) HPAH PASMCs, 2) Bmpr2(+/-) 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-beta1. This was not associated with altered canonical TGF-beta1/Smad signaling but was associated with a secreted factor. Microarray analysis revealed that the transcriptional responses to TGF-beta1 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-beta1, an effect reversed by NF-kappaB inhibition. Moreover, neutralizing antibodies to IL-6 or IL-8 restored the antiproliferative effect of TGF-beta1 in HPAH PASMCs. This study establishes that BMPR-II deficiency leads to failed growth suppression by TGF-beta1 in PASMCs. This effect is Smad-independent but is associated with inappropriately altered NF-kappaB 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-beta1. |
