An antiproliferative BMP-2/PPARγ/apoE axis in human and murine SMCs and its role in pulmonary hypertension
Open accessAbstract
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.
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The mechanism of BMP2-mediated upregulation of ApoE operates through a novel PPARγ/ApoE axis downstream of BMP2 and its receptor BMP-R2; BMP2/BMP-R2 signaling leads to activation of PPARγ and resulting production and secretion of ApoE.
“The mechanism of BMP2-mediated upregulation of ApoE is operated through a novel PPARγ/ApoE axis down stream of BMP2 and its receptor, BMP-R2. The BMP2/BMP-R2 signaling leads to activation of PPARγ and the resulting production and secretion of ApoE [43].”
From Genome-wide analysis identifies novel loci influencing plasma apolipoprotein E concentration and Alzheimer’s disease risk (2023) · cites this paper as [43]
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Ishihara, K., Tsutsumi, K., Kawane, S., Nakajima, M., & Kasaoka, T. (2003) · FEBS Letters · doi:10.1016/s0014-5793(03)00846-9 · Cited by 201 · see citing works
PPARγ ligand attenuates PDGF-induced mesangial cell proliferation: Role of MAP kinase
Ghosh, S. S., Gehr, T. W. B., Ghosh, S., Fakhry, I., Sica, D. A., Lyall, V., & Schoolwerth, A. C. (2003) · Kidney International · doi:10.1046/j.1523-1755.2003.00054.x · Cited by 53 · see citing works
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Inflammation and immunity in the pathogenesis of pulmonary arterial hypertension
Rabinovitch, M., Guignabert, C., Humbert, M., & Nicolls, M. R. (2014) · Circulation Research · doi:10.1161/circresaha.113.301141 · Cited by 1,029 · see citing works
Self-citationThe nox4 inhibitor gkt137831 attenuates hypoxia-induced pulmonary vascular cell proliferation
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Obesity, estrogens and adipose tissue dysfunction - implications for pulmonary arterial hypertension
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Linden, A. K., Affaneh, A., Aylward, A., Wong, Y., Kessler, J. A., & Peng, C.-Y. (2025) · doi:10.64898/2025.12.14.694212 · Cited by 1 · see citing works
- Authors
- Hansmann, G., de Jesus Perez, V. A., Alastalo, T.-P., Alvira, C. M., Guignabert, C., Bekker, J. M., Schellong, S., Urashima, T., Wang, L., Morrell, N. W., & Rabinovitch, M.
- Affiliations
- Stanford Medicine (US)
- University of Cambridge (GB)
- Corresponding author
- Rabinovitch, Marlene
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2008-05-01
- Volume
- 118
- Issue
- 5
- Pages
- 1846-1857
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC2276393
- OpenAlex
- W2146888695
- Cited by
- 367
- References
- 2
- Citations by year
- 2026: 10 · 2025: 15 · 2024: 20 · 2023: 11 · 2022: 11 · 2021: 15 · 2020: 16 · 2019: 17 · 2018: 27 · 2017: 17 · 2016: 24 · 2015: 30 · 2014: 28 · 2013: 28 · 2012: 29
- FWCI
- 19.98
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Heart Association
- British Heart Foundation
- National Institutes of Health (5r01hl074186-17, HL074186)
- National Heart, Lung, and Blood Institute (R01-HL074186, 1R01 HL 074186-01, T32HL007708, R01HL087118, 2-T32-HL007708-14)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Pulmonary Hypertension Research and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Keywords
- pulmonary arterial hypertension, BMP-2, PPARγ, apolipoprotein E, smooth muscle cell proliferation, PDGF-BB, ERK signaling, Smad-independent signaling, PPARγ knockout mice, pulmonary artery muscularization, PPARγ agonists
- MeSH terms
- Rosiglitazone, Becaplermin, Animals, Apolipoproteins E, Cells, Cultured, Hemodynamics, Humans, Hypertension, Pulmonary, Hypoglycemic Agents, Mice, Transgenic, Muscle, Smooth, Vascular, Platelet-Derived Growth Factor, Signal Transduction, Transforming Growth Factor beta, Mice, Knockout, Bone Morphogenetic Proteins, Proto-Oncogene Proteins c-sis, Myocytes, Smooth Muscle, RNA Interference, Thiazolidinediones, PPAR gamma, Extracellular Signal-Regulated MAP Kinases, Mice, Bone Morphogenetic Protein Receptors, Type II, Bone Morphogenetic Protein 2
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