The Noncanonical WNT Pathway Is Operative in Idiopathic Pulmonary Arterial Hypertension

Laumanns, I; Fink, Ludger; Wilhelm, Jochen; Wolff, Jens-C.; Mitnacht-Kraus, Rita; Graef-Hoechst, Sabine; Stein, Maria Magdalena; Bohle, Rainer M.; Klepetko, Walter; Hoda, Mir Ali Reza; Schermuly, Ralph Theo; Grimminger, Friedrich; Seeger, Werner; Voswinckel, Robert

doi:10.1165/rcmb.2008-0153oc

Cited by 90 publications

(94 citation statements)

References 71 publications

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“…The Wnt signaling pathway influences cell-cell communication, adult tissue maintenance, and gene expression. BMPR2 signaling may regulate both canonical and noncanonical Wnt pathways in EC and MC to influence proliferation, survival, and motility during angiogenesis and remodeling of the pulmonary circulation (3,19,39). While the relationship of BMPR2 and Wnt pathways has been defined during development, the regulatory targets of Wnt signaling, common across multiple cell types, in BMPR2-associated PAH are unknown.…”

Section: Discussionmentioning

confidence: 99%

“…In one study of PAH lung tissue, of ϳ14,000 genes with measurable expression, 13,889 were altered (57). Among studies of PAH patient-derived samples, there have been three studies of lung tissue specimens (28,39,57), four studies of freshly isolated circulating cells (11,30,56,63), and three studies of cells cultured from PAH patients (5,24,65). While the overall results have been recently reviewed (48), we reexamined these data to determine whether they also identified alterations in expression of Wnt signaling molecules as a disease-associated signaling pathway (Table 2).…”

Section: Discussionmentioning

confidence: 99%

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Identification of a common Wnt-associated genetic signature across multiple cell types in pulmonary arterial hypertension

West

Austin

Gaskill

et al. 2014

American Journal of Physiology-Cell Physiology

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May 28, 2014; doi:10.1152/ajpcell.00057.2014.-Understanding differences in gene expression that increase risk for pulmonary arterial hypertension (PAH) is essential to understanding the molecular basis for disease. Previous studies on patient samples were limited by end-stage disease effects or by use of nonadherent cells, which are not ideal to model vascular cells in vivo. These studies addressed the hypothesis that pathological processes associated with PAH may be identified via a genetic signature common across multiple cell types. Expression array experiments were initially conducted to analyze cell types at different stages of vascular differentiation (mesenchymal stromal and endothelial) derived from PAH patient-specific induced pluripotent stem (iPS) cells. Molecular pathways that were altered in the PAH cell lines were then compared with those in fibroblasts from 21 patients, including those with idiopathic and heritable PAH. Wnt was identified as a target pathway and was validated in vitro using primary patient mesenchymal and endothelial cells. Taken together, our data suggest that the molecular lesions that cause PAH are present in all cell types evaluated, regardless of origin, and that stimulation of the Wnt signaling pathway was a common molecular defect in both heritable and idiopathic PAH. pulmonary arterial hypertension; gene array; induced pluripotent stem cell; mesenchymal stromal cell; endothelial cell; heritable pulmonary arterial hypertension; idiopathic pulmonary arterial hypertension; Wnt signaling PULMONARY ARTERIAL HYPERTENSION (PAH) is characterized by vascular remodeling, including endothelial cell (EC) dysfunction and occlusion or rarefaction of the peripheral pulmonary microvasculature. More recently, the contribution of multipotent mesenchymal stromal cells (MSC) to muscularization of microvessels has been described (13). The interactions between the lung microenvironment, vascular EC, and MSC during remodeling in PAH remain unclear. All forms of PAH have a high mortality rate, despite current therapeutic options.Deregulated bone morphogenetic protein (BMP) receptor type II (BMPR2) signaling is strongly associated with the development of PAH in both heritable (BMPR2 mut and Cav1 mut ) and idiopathic cases, although the molecular mechanisms through which BMPR2 derangement promotes PAH are unknown. Unfortunately, most rodent models of PAH do not precisely recapitulate the disease pathology; these models display less substantial pulmonary vascular remodeling in both proximal arteries and distal microvasculature, significantly slowing drug discovery efforts. Current in vitro models overexpressing mutant BMPR2 in cell types of interest are complicated by persistent retention of wild-type (WT) signaling. Moreover, human PAH tissue is limited in quantity, and specimens are typically obtained posttransplant or at autopsy, which limits conclusions about disease initiation and propagation. Previous global gene expression analyses using patient samples to identify risk factors for PAH have ...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Identification of a common Wnt-associated genetic signature across multiple cell types in pulmonary arterial hypertension

West

Austin

Gaskill

et al. 2014

American Journal of Physiology-Cell Physiology

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“…Data from this study combined with this background highlight the potential roles for miR-15a, miR19a, and miR-21 in SCD-related PH and further validate the miRNA signature for an elevated TRV in SCD. Pathway analyses of the differentially regulated genes for an elevated TRV comparison set revealed involvement of established PH processes, including Wnt signaling, calcium signaling, vascular smooth muscle contraction, cancer pathways, and primary bile acid biosynthesis pathways (41)(42)(43)(44), although these have yet to be explored in PH associated with SCD. Axon guidance and NOD-like receptor signaling appear to represent novel pathways involved in the elevated TRV phenotype.…”

Section: Discussionmentioning

confidence: 99%

A Novel Molecular Signature for Elevated Tricuspid Regurgitation Velocity in Sickle Cell Disease

Desai¹,

Zhou²,

Ahmad

et al. 2012

Am J Respir Crit Care Med

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Rationale: An increased tricuspid regurgitation jet velocity (TRV . 2.5 m/s) and pulmonary hypertension defined by right heart catheterization both independently confer increased mortality in sickle cell disease (SCD). Objectives: We explored the usefulness of peripheral blood mononuclear cell-derived gene signatures as biomarkers for an elevated TRV in SCD. Methods: Twenty-seven patients with SCD underwent echocardiography and peripheral blood mononuclear cell isolation for expression profiling and 112 patients with SCD were genotyped for single-nucleotide polymorphisms. Measurements and Main Results: Genome-wide gene and miRNA expression profiles were correlated against TRV, yielding 631 transcripts and 12 miRNAs. Support vector machine analysis identified a 10-gene signature including GALNT13 (encoding polypeptide N-acetylgalactosaminyltransferase 13) that discriminates patients with and without increased TRV with 100% accuracy. This finding was then validated in a cohort of patients with SCD without (n ¼ 10) and with pulmonary hypertension (n ¼ 10, 90% accuracy). Increased TRV-related miRNAs revealed strong in silico binding predictions of miR-301a to GALNT13 corroborated by microarray analyses demonstrating an inverse correlation between their expression. A genetic association study comparing patients with an elevated (n ¼ 49) versus normal (n ¼ 63) TRV revealed five significant single-nucleotide polymorphisms within GALNT13 (P , 0.005), four trans-acting (P , 2.1 3 10 27) and one cis-acting (P ¼ 0.6 3 10 24 ) expression quantitative trait locus upstream of the adenosine-A2B receptor gene (ADORA2B). Conclusions: These studies validate the clinical usefulness of genomic signatures as potential biomarkers and highlight ADORA2B and GALNT13 as potential candidate genes in SCD-associated elevated TRV.

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“…This finding is in agreement with recent studies that have suggested an important role of LRP5/6 and Wnt/β-catenin signaling in vascular smooth muscle cell development and PH. Gene expression analysis of pulmonary arterial resistance vessels revealed differentially regulated canonical and noncanonical Wnt genes in PH (13,19,27,30,31).…”

Section: Mesd and Hyperoxic Neonatal Lung Injurymentioning

confidence: 99%

Inhibition of LRP5/6-mediated Wnt/β-catenin signaling by Mesd attenuates hyperoxia-induced pulmonary hypertension in neonatal rats

et al. 2013

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Background: Hyperoxia-induced neonatal lung injury is associated with activation of Wnt/β-catenin signaling. Lowdensity lipoprotein receptor-related proteins 5 and 6 (LRP5/6) are Wnt coreceptors that bind to Wnt ligands and mediate canonical Wnt/β-catenin signaling. We hypothesized that inhibition of LRP5/6 by their universal inhibitor, Mesd, would attenuate hyperoxia-induced lung injury. Methods: Newborn rat pups were randomly exposed to normoxia or hyperoxia at 90% FiO 2 and injected intraperitoneally with placebo or Mesd every other day for 14 d. On day 15, phosphorylation of LRP5/6 (pLRP5/6), expression of Wnt/ β-catenin target genes, cyclin D1 and Wnt-induced signaling protein-1 (WISP-1), right-ventricular systolic pressure (RVSP), right-ventricular hypertrophy (RVH), pulmonary vascular remodeling, alveolarization, and vascularization were measured. results: Hyperoxia exposure markedly induced pLRP5/6, cyclin D1, and WISP-1 expression in the lungs of placebo animals, but they were significantly attenuated by the administration of Mesd. Mesd also significantly attenuated hyperoxiainduced pulmonary hypertension (PH) and pulmonary vascular remodeling. However, there was no effect on alveolarization or vascularization after Mesd administration. conclusion: This study demonstrates that LRP5/6 mediates pulmonary vascular remodeling and PH in hyperoxia-induced neonatal lung injury, thereby suggesting a potential therapeutic target to alleviate PH in neonates with severe bronchopulmonary dysplasia.

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The Noncanonical WNT Pathway Is Operative in Idiopathic Pulmonary Arterial Hypertension

Cited by 90 publications

References 71 publications

Identification of a common Wnt-associated genetic signature across multiple cell types in pulmonary arterial hypertension

Identification of a common Wnt-associated genetic signature across multiple cell types in pulmonary arterial hypertension

A Novel Molecular Signature for Elevated Tricuspid Regurgitation Velocity in Sickle Cell Disease

Inhibition of LRP5/6-mediated Wnt/β-catenin signaling by Mesd attenuates hyperoxia-induced pulmonary hypertension in neonatal rats

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