ArticleAmerican journal of respiratory cell and molecular biology2016
Bone Morphogenic Protein Type 2 Receptor Mutation-Independent Mechanisms of Disrupted Bone Morphogenetic Protein Signaling in Idiopathic Pulmonary Arterial Hypertension.
Article in American journal of respiratory cell and molecular biology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 25 citations in OpenAlex.
- Emerging significance of E3 ubiquitin ligases and Deubiquitinases in pulmonary hypertension.Molecular medicine (Cambridge, Mass.) · 2026Review
- Article
- Fundamental and Targeted Approaches in Pulmonary Arterial Hypertension Treatment.Pharmaceutics · 2025Review
- Characteristic disease defects in circulating endothelial cells isolated from patients with pulmonary arterial hypertension.PloS one · 2024Article
- Small-Molecule Probes as Pharmacological Tools for the Bone Morphogenetic Protein Signaling Pathway.ACS pharmacology & translational science · 2023Review
- Adipokines in pulmonary hypertension: angels or demons?Heliyon · 2023Review
- The Glycobiology of Pulmonary Arterial Hypertension.Metabolites · 2022Review
- Sex Dimorphism in Pulmonary Hypertension: The Role of the Sex Chromosomes.Antioxidants (Basel, Switzerland) · 2021Review
- Article
- 'There and Back Again'-Forward Genetics and Reverse Phenotyping in Pulmonary Arterial Hypertension.Genes · 2020Review
- Article
- Treatment With Treprostinil and Metformin Normalizes Hyperglycemia and Improves Cardiac Function in Pulmonary Hypertension Associated With Heart Failure With Preserved Ejection Fraction.Arteriosclerosis, thrombosis, and vascular biology · 2020Article
- O-GlcNAc Transferase Regulates Angiogenesis in Idiopathic Pulmonary Arterial Hypertension.International journal of molecular sciences · 2019Article
- Pathology and pathobiology of pulmonary hypertension: state of the art and research perspectives.The European respiratory journal · 2019Review
- EXPRESS: Gremlin1 blocks vascular endothelial growth factor signalling in the pulmonary microvascular endothelium.Pulmonary circulation · 2018Article
- Update in Pulmonary Vascular Disease 2016 and 2017.American journal of respiratory and critical care medicine · 2018Article
- Pulmonary Hypertension and Precision Medicine through the "Omics" Looking Glass.American journal of respiratory and critical care medicine · 2017Article
- Molecular and functional characterization of the BMPR2 gene in Pulmonary Arterial Hypertension.Scientific reports · 2017Article
- Novel methods in pulmonary hypertension phenotyping in the age of precision medicine (2015 Grover Conference series).Pulmonary circulation · 2016Review
- Cytokines trigger disruption of endothelium barrier function and p38 MAP kinase activation inPulmonary circulationArticle
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Authors and funding
11 authors at 4 institutions in 2 countries.
Funding
Abstract
Altered bone morphogenic protein (BMP) signaling, independent of BMPR2 mutations, can result in idiopathic pulmonary arterial hypertension (IPAH). Glucose dysregulation can regulate multiple processes in IPAH. However, the role of glucose in BMP antagonist expression in IPAH has not been characterized. We hypothesized that glucose uptake regulates BMP signaling through stimulation of BMP antagonist expression in IPAH. Using human plasma, lung tissue, and primary pulmonary arterial smooth muscle cells (PASMCs), we examined the protein expression of BMP2, BMP-regulated Smads, and Smurf-1 in patients with IPAH and control subjects. Gremlin-1 levels were elevated in patients with IPAH compared with control subjects, whereas expression of BMP2 was not different. We demonstrate increased Smad polyubiquitination in IPAH lung tissue and PASMCs that was further enhanced with proteasomal inhibition. Examination of the Smad ubiquitin-ligase, Smurf-1, showed increased protein expression in IPAH lung tissue and localization in the smooth muscle of the pulmonary artery. Glucose dose dependently increased Smurf-1 protein expression in control PASMCs, whereas Smurf-1 in IPAH PASMCs was increased and sustained. Conversely, phospho-Smad1/5/8 levels were reduced in IPAH compared with control PASMCs at physiological glucose concentrations. Interestingly, high glucose concentrations decreased phosphorylation of Smad1/5/8 in control PASMCs. Blocking glucose uptake had opposing effects in IPAH PASMCs, and inhibition of Smurf-1 activity resulted in partial rescue of Smad1/5/8 activation and cell migration rates. Collectively, these data suggest that BMP signaling can be regulated through BMPR2 mutation-independent mechanisms. Gremlin-1 (synonym: induced-in-high-glucose-2 protein) and Smurf-1 may function to inhibit BMP signaling as a consequence of the glucose dysregulation described in IPAH.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.