[HTML][HTML] An antiproliferative BMP-2/PPARγ/apoE axis in human and murine SMCs and its role in pulmonary hypertension

G Hansmann, VA de Jesus Perez… - The Journal of …, 2008 - Am Soc Clin Investig
G Hansmann, VA de Jesus Perez, TP Alastalo, CM Alvira, C Guignabert, JM Bekker…
The Journal of clinical investigation, 2008Am Soc Clin Investig
Loss-of-function mutations in bone morphogenetic protein receptor II (BMP-RII) are linked to
pulmonary arterial hypertension (PAH); the ligand for BMP-RII, BMP-2, is a negative
regulator of SMC growth. Here, we report an interplay between PPARγ and its transcriptional
target apoE downstream of BMP-2 signaling. BMP-2/BMP-RII signaling prevented PDGF-BB–
induced proliferation of human and murine pulmonary artery SMCs (PASMCs) by
decreasing nuclear phospho-ERK and inducing DNA binding of PPARγ that is independent …
Loss-of-function mutations in bone morphogenetic protein receptor II (BMP-RII) are linked to pulmonary arterial hypertension (PAH); the ligand for BMP-RII, BMP-2, is a negative regulator of SMC growth. Here, we report an interplay between PPARγ and its transcriptional target apoE downstream of BMP-2 signaling. BMP-2/BMP-RII signaling prevented PDGF-BB–induced proliferation of human and murine pulmonary artery SMCs (PASMCs) by decreasing nuclear phospho-ERK and inducing DNA binding of PPARγ that is independent of Smad1/5/8 phosphorylation. Both BMP-2 and a PPARγ agonist stimulated production and secretion of apoE by SMCs. Using a variety of methods, including short hairpin RNAi in human PASMCs, PAH patient–derived BMP-RII mutant PASMCs, a PPARγ antagonist, and PASMCs isolated from PPARγ- and apoE-deficient mice, we demonstrated that the antiproliferative effect of BMP-2 was BMP-RII, PPARγ, and apoE dependent. Furthermore, we created mice with targeted deletion of PPARγ in SMCs and showed that they spontaneously developed PAH, as indicated by elevated RV systolic pressure, RV hypertrophy, and increased muscularization of the distal pulmonary arteries. Thus, PPARγ-mediated events could protect against PAH, and PPARγ agonists may reverse PAH in patients with or without BMP-RII dysfunction.
The Journal of Clinical Investigation