ArticleThe Journal of biological chemistry2013
A novel p38 mitogen-activated protein kinase/Elk-1 transcription factor-dependent molecular mechanism underlying abnormal endothelial cell proliferation in plexogenic pulmonary arterial hypertension.
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 37 citations in OpenAlex.
- Molecular mechanisms of EPAS1 in regulating pulmonary vascular remodeling in COPD: a review.Molecular biology reports · 2026Review
- Endocytic Adaptor Proteins in Vascular Diseases: Critical Role of Intracellular Trafficking in Regulating Pathobiology of Vascular Disorders.Cardiology discovery · 2026Review
- Signaling pathways and targeted therapy for pulmonary hypertension.Signal transduction and targeted therapy · 2025Review
- Dysregulation of the Long Noncoding RNA X-Inactive-Specific Transcript Expression in Male Patients with Pulmonary Arterial Hypertension.The American journal of pathology · 2024Article
- Case Report: Identification of microduplication in the chromosomal 2p16.1p15 region in an infant suffering from pulmonary arterial hypertension.Frontiers in cardiovascular medicine · 2023Article
- Long noncoding RNAGenes & diseases · 2022Review
- Molecular basis of the association between transcription regulators nuclear respiratory factor 1 and inhibitor of DNA binding protein 3 and the development of microvascular lesions.Microvascular research · 2022Review
- The Impact of Sex Chromosomes in the Sexual Dimorphism of Pulmonary Arterial Hypertension.The American journal of pathology · 2022Review
- Shufeiya Recipe Improves Monocrotaline-Induced Pulmonary Hypertension in Rats by Regulating SIRT3/FOXO3a and Its Downstream Signaling Pathways.Disease markers · 2022Article
- Transcription factors in the pathogenesis of pulmonary arterial hypertension-Current knowledge and therapeutic potential.Frontiers in cardiovascular medicine · 2022Review
- Endothelial cells in the pathogenesis of pulmonary arterial hypertension.The European respiratory journal · 2021Review
- Up-Regulation of the Long Noncoding RNA X-Inactive-Specific Transcript and the Sex Bias in Pulmonary Arterial Hypertension.The American journal of pathology · 2021Article
- Sex Dimorphism in Pulmonary Hypertension: The Role of the Sex Chromosomes.Antioxidants (Basel, Switzerland) · 2021Review
- Sex differences in the proliferation of pulmonary artery endothelial cells: implications for plexiform arteriopathy.Journal of cell science · 2020Article
- Early progression of pulmonary hypertension in the monocrotaline model in males is associated with increased lung permeability.Biology of sex differences · 2020Article
- Phenotype-Based Screens with Conformation-Specific Inhibitors Reveal p38 Gamma and Delta as Targets for HCC Polypharmacology.Molecular cancer therapeutics · 2019Article
- Plexiform Arteriopathy in Rodent Models of Pulmonary Arterial Hypertension.The American journal of pathology · 2019Review
- Alk5/Runx1 signaling mediated by extracellular vesicles promotes vascular repair in acute respiratory distress syndrome.Clinical and translational medicine · 2018Article
- Epsin15 Homology Domains: Role in the Pathogenesis of Pulmonary Arterial Hypertension.Frontiers in physiology · 2018Article
- Intersectin-1s deficiency in pulmonary pathogenesis.Respiratory research · 2017Review
Corrections and comments
- Erratum issuedRyan-Hemnes, Anna [corrected to Hemnes, Anna Ryan]
Authors and funding
14 authors at 6 institutions in 1 country.
Funding
Abstract
Plexiform lesions (PLs), the hallmark of plexogenic pulmonary arterial hypertension (PAH), contain phenotypically altered, proliferative endothelial cells (ECs). The molecular mechanism that contributes to EC proliferation and formation of PLs is poorly understood. We now show that a decrease in intersectin-1s (ITSN-1s) expression due to granzyme B (GrB) cleavage during inflammation associated with PAH and the high p38/Erk1/2(MAPK) activity ratio caused by the GrB/ITSN cleavage products lead to EC proliferation and selection of a proliferative/plexiform EC phenotype. We used human pulmonary artery ECs of PAH subjects (EC(PAH)), paraffin-embedded and frozen human lung tissue, and animal models of PAH in conjunction with microscopy imaging, biochemical, and molecular biology approaches to demonstrate that GrB cleaves ITSN-1s, a prosurvival protein of lung ECs, and generates two biologically active fragments, an N-terminal fragment (GrB-EH(ITSN)) with EC proliferative potential and a C-terminal product with dominant negative effects on Ras/Erk1/2. The proliferative potential of GrB-EH(ITSN) is mediated via sustained phosphorylation of p38(MAPK) and Elk-1 transcription factor and abolished by chemical inhibition of p38(MAPK). Moreover, lung tissue of PAH animal models and human specimens and EC(PAH) express lower levels of ITSN-1s compared with controls and the GrB-EH(ITSN) cleavage product. Moreover, GrB immunoreactivity is associated with PLs in PAH lungs. The concurrent expression of the two cleavage products results in a high p38/Erk1/2(MAPK) activity ratio, which is critical for EC proliferation. Our findings identify a novel GrB-EH(ITSN)-dependent pathogenic p38(MAPK)/Elk-1 signaling pathway involved in the poorly understood process of PL formation in severe PAH.
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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 OpenQuestion graph.