An antiproliferative BMP-2/PPARgamma/apoE axis in human and murine SMCs and its role in pulmonary hypertension.
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 PPARgamma 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 PPARgamma that is independent of Smad1/5/8 phosphorylation. Both BMP-2 and a PPARgamma 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 PPARgamma antagonist, and PASMCs isolated from PPARgamma- and apoE-deficient mice, we demonstrated that the antiproliferative effect of BMP-2 was BMP-RII, PPARgamma, and apoE dependent. Furthermore, we created mice with targeted deletion of PPARgamma 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, PPARgamma-mediated events could protect against PAH, and PPARgamma agonists may reverse PAH in patients with or without BMP-RII dysfunction.
Hansmann
Georg
G
Department of Pediatrics, Stanford University School of Medicine, Stanford, California 94305-5162, USA.
de Jesus Perez
Vinicio A
VA
Alastalo
Tero-Pekka
TP
Alvira
Cristina M
CM
Guignabert
Christophe
C
Bekker
Janine M
JM
Schellong
Stefan
S
Urashima
Takashi
T
Wang
Lingli
L
Morrell
Nicholas W
NW
Rabinovitch
Marlene
M
D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism*; D000077214:Becaplermin; D055396:Bone Morphogenetic Protein 2; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics / Q000378:metabolism*; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D006439:Hemodynamics; D006801:Humans; D006976:Hypertension, Pulmonary / Q000378:metabolism* / Q000503:physiopathology; D007004:Hypoglycemic Agents / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism*; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis; D034622:RNA Interference; D000077154:Rosiglitazone; D015398:Signal Transduction / Q000502:physiology; D045162:Thiazolidinediones / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
D001057:Apolipoproteins E; C525718:BMP2 protein, human; C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D045162:Thiazolidinediones; D016212:Transforming Growth Factor beta; D000077154:Rosiglitazone; D000077214:Becaplermin; D048049:Extracellular Signal-Regulated MAP Kinases; D052006:Bone Morphogenetic Protein Receptors, Type II