Bone Morphogenetic Protein Receptor Type II Deficiency and Increased Inflammatory Cytokine Production. A Gateway to Pulmonary Arterial Hypertension

Soon, Elaine; Crosby, Alexi; Southwood, Mark; Yang, Peiran; Tajsic, Tamara; Toshner, Mark; Appleby, Sarah; Shanahan, Catherine M.; Bloch, Kenneth D.; Pepke‐Zaba, Joanna; Upton, Paul D.; Morrell, Nicholas W.

doi:10.1164/rccm.201408-1509oc

Cited by 124 publications

(116 citation statements)

References 61 publications

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“…However, the exact contribution of either ROS sources to PH development remains to be elucidated. The importance of prooxidative metabolism in PH is supported by studies where suppression of oxidative metabolism, including the use of tempol, leads to the reduction of PH development (24)(25)(26)(43)(44)(45).…”

Section: Discussionmentioning

confidence: 99%

Constitutive Reprogramming of Fibroblast Mitochondrial Metabolism in Pulmonary Hypertension

Plecitá–Hlavatá

Tauber

et al. 2016

Am J Respir Cell Mol Biol

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Remodeling of the distal pulmonary artery wall is a characteristic feature of pulmonary hypertension (PH). In hypoxic PH, the most substantial pathologic changes occur in the adventitia. Here, there is marked fibroblast proliferation and profound macrophage accumulation. These PH fibroblasts (PH-Fibs) maintain a hyperproliferative, apoptotic-resistant, and proinflammatory phenotype in ex vivo culture. Considering that a similar phenotype is observed in cancer cells, where it has been associated, at least in part, with specific alterations in mitochondrial metabolism, we sought to define the state of mitochondrial metabolism in PH-Fibs. In PH-Fibs, pyruvate dehydrogenase was markedly inhibited, resulting in metabolism of pyruvate to lactate, thus consistent with a Warburg-like phenotype. In addition, mitochondrial bioenergetics were suppressed and mitochondrial fragmentation was increased in PH-Fibs. Most importantly, complex I activity was substantially decreased, which was associated with down-regulation of the accessory subunit nicotinamide adenine dinucleotide reduced dehydrogenase (ubiquinone) Fe-S protein 4 (NDUFS4). Owing to less-efficient ATP synthesis, mitochondria were hyperpolarized and mitochondrial superoxide production was increased. This pro-oxidative status was further augmented by simultaneous induction of cytosolic nicotinamide adenine dinucleotide phosphate reduced oxidase 4. Although acute and chronic exposure to hypoxia of adventitial fibroblasts from healthy control vessels induced increased glycolysis, it did not induce complex I deficiency as observed in PH-Fibs. This suggests that hypoxia alone is insufficient to induce NDUFS4 down-regulation and constitutive abnormalities in complex I. In conclusion, our study provides evidence that, in the pathogenesis of vascular remodeling in PH, alterations in fibroblast mitochondrial metabolism drive distinct changes in cellular behavior, which potentially occur independently of hypoxia.

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Section: Discussionmentioning

confidence: 99%

Constitutive Reprogramming of Fibroblast Mitochondrial Metabolism in Pulmonary Hypertension

Plecitá–Hlavatá

Tauber

et al. 2016

Am J Respir Cell Mol Biol

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“…Interestingly there is increasing evidence, suggesting a link between mutations in the BMPR2 gene, which is associated with an increased risk for PAH, and inflammation. Recently it has been reported that BMPR2 deficiency increases the LPS stimulated lung and circulatory IL-6 and IL-8 production, in patients with BMPR2 deficiency as compared to control subjects (125). In an earlier study it was shown that there is a negative feedback loop between IL-6 and BMPR2 signaling, both in vitro and in vivo.…”

Section: Pulmonary Hypertension and Inflammationmentioning

confidence: 99%

The mast cell–B cell axis in lung vascular remodeling and pulmonary hypertension

Breitling

Zhou

Zabini

et al. 2017

American Journal of Physiology-Lung Cellular and Molecular Phys

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Over past years, a critical role for the immune system and, in particular, for mast cells in the pathogenesis of pulmonary hypertension (PH) has emerged. However, the way in which mast cells promote PH is still poorly understood. Here, we investigated the mechanisms by which mast cells may contribute to PH, specifically focusing on the interaction between the innate and adaptive immune response and the role of B cells and autoimmunity. Experiments were performed in Sprague-Dawley rats and B cell-deficient JH-KO rats in the monocrotaline, Sugen/hypoxia, and the aortic banding model of PH. Hemodynamics, cell infiltration, IL-6 expression, and vascular remodeling were analyzed. Gene array analyses revealed constituents of immunoglobulins as most prominently regulated mast cell-dependent genes in the lung in experimental PH. IL-6 was shown to link mast cells to B cells, as 1) IL-6 was upregulated and colocalized with mast cells and was reduced by mast-cell stabilizers and 2) IL-6 or mast cell blockade reduced B cells in lungs of monocrotaline-treated rats. A functional role for B cells in PH was demonstrated in that either blocking B cells by an anti-CD20 antibody or B-cell deficiency in JH-KO rats attenuated right ventricular systolic pressure and vascular remodeling in experimental PH. We here identify a mast cell–B cell axis driven by IL-6 as a critical immune pathway in the pathophysiology of PH. Our results provide novel insights into the role of the immune system in PH, which may be therapeutically exploited by targeted immunotherapy.

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“…43,44 Future studies should also address the role of NETs in the pathogenesis of PH and investigate whether neutrophils from PAH and CTEPH patients show increased propensity to form NETs. This would not be entirely unexpected because PAH and CTEPH neutrophils respond to stimulation with increased inflammatory mediator generation ex vivo, including increased respiratory burst, elastase secretion, and lipid mediator synthesis.…”

Section: Pad4mentioning

confidence: 99%

Neutrophil Extracellular Traps Promote Angiogenesis

Aldabbous

Abdul-Salam

McKinnon

et al. 2016

ATVB

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173

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Objective— Inflammation and dysregulated angiogenesis are features of endothelial dysfunction in pulmonary hypertension. Neutrophil extracellular traps (NETs), produced by dying neutrophils, contribute to pathogenesis of numerous vascular disorders but their role in pulmonary hypertension has not been studied. We sought evidence of (NETs) formation in pulmonary hypertension and investigated the effect of NETs on endothelial function. Approach and Results— Plasma and lung tissues of patients with pulmonary hypertension were analyzed for NET markers. The effects of NETs on endothelial function were studied in vitro and in vivo. Patients with chronic thromboembolic pulmonary hypertension and idiopathic pulmonary hypertension showed elevated plasma levels of DNA, neutrophil elastase, and myeloperoxidase. NET-forming neutrophils and extensive areas of NETosis were found in the occlusive plexiform lesions and vascularized intrapulmonary thrombi. NETs induced nuclear factor κB–dependent endothelial angiogenesis in vitro and increased vascularization of matrigel plugs in vivo. Angiogenic responses were associated with increased release of matrix metalloproteinase-9, heparin-binding epidermal growth factor–like growth factor, latency-associated peptide of the transforming growth factor β1, and urokinase-type plasminogen activator, accompanied by increased endothelial permeability and cell motility. NETs-induced responses depended on myeloperoxidase/H 2 O 2 -dependent activation of Toll-like receptor 4/nuclear factor κB signaling. NETs stimulated the release of endothelin-1 in HPAECs (human pulmonary artery endothelial cells) and stimulated pulmonary smooth muscle cell proliferation in vitro. Conclusions— We are the first to implicate NETs in angiogenesis and provide a functional link between NETs and inflammatory angiogenesis in vitro and in vivo. We demonstrate the potential pathological relevance of this in 2 diseases of disordered vascular homeostasis, pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension.

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Bone Morphogenetic Protein Receptor Type II Deficiency and Increased Inflammatory Cytokine Production. A Gateway to Pulmonary Arterial Hypertension

Cited by 124 publications

References 61 publications

Constitutive Reprogramming of Fibroblast Mitochondrial Metabolism in Pulmonary Hypertension

Constitutive Reprogramming of Fibroblast Mitochondrial Metabolism in Pulmonary Hypertension

The mast cell–B cell axis in lung vascular remodeling and pulmonary hypertension

Neutrophil Extracellular Traps Promote Angiogenesis

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