Aberrant Chloride Intracellular Channel 4 Expression Contributes to Endothelial Dysfunction in Pulmonary Arterial Hypertension

Wójciak-Stothard, Beata; Abdul-Salam, Vahitha B.; Lao, Ka Hou; Tsang, Hon Ki; Irwin, David; Lisk, Christina; Loomis, Zoe; Stenmark, Kurt R.; Edwards, John C.; Yuspa, Stuart H.; Howard, Luke; Edwards, Robert J.; Rhodes, Christopher J.; Gibbs, J. Simon R.; Wharton, John; Zhao, Lan; Wilkins, Martin R.

doi:10.1161/circulationaha.113.006797

Cited by 62 publications

(88 citation statements)

References 41 publications

(63 reference statements)

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“…25 Interestingly, activation of TLR4 by NETs was accompanied by increased expression of CLIC4 in HPAECs, consistent with the proinflammatory and proangiogenic phenotype ( Figure 5F). …”

Section: Toll-like Receptor 4 Mediates the Proinflammatory And Proangsupporting

confidence: 62%

“…The link between CLIC4 and TLR4 signaling will require further studies, but CLIC4 was shown to increase phosphorylation of p65 subunit of NFκB, important for the NFκB-induced hypoxia-inducible factor activation and pulmonary endothelial angiogenesis in vitro. 25 Having demonstrated that NETs increase pulmonary endothelial cell motility and angiogenic responses in vitro, we then investigated the angiogenic effects of NETs in vivo.…”

Section: Discussionmentioning

confidence: 99%

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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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“…25 Interestingly, activation of TLR4 by NETs was accompanied by increased expression of CLIC4 in HPAECs, consistent with the proinflammatory and proangiogenic phenotype ( Figure 5F). …”

Section: Toll-like Receptor 4 Mediates the Proinflammatory And Proangsupporting

confidence: 62%

Section: Discussionmentioning

confidence: 99%

Neutrophil Extracellular Traps Promote Angiogenesis

Aldabbous

Abdul-Salam

McKinnon

et al. 2016

ATVB

Self Cite

173

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“…This function of CLIC1 is resembled by a close relative, CLIC4, which mediates acidification of vacuoles in endothelial cells (34). However, it is important to note that CLIC4 has a number of additional functions, which do not seem to depend on anion currents, including the stabilization of phospho-smad2/3 as well as the p65 subunit of NFκB (35, 36). The interaction of CLIC4 with NFκB in endothelial cells is significant for pulmonary hypertension as it leads to activation of HIF1α and induction of an overall mesenchymal phenotype with invadopodia and stress fibers (36).…”

Section: Discussionmentioning

confidence: 99%

“…However, it is important to note that CLIC4 has a number of additional functions, which do not seem to depend on anion currents, including the stabilization of phospho-smad2/3 as well as the p65 subunit of NFκB (35, 36). The interaction of CLIC4 with NFκB in endothelial cells is significant for pulmonary hypertension as it leads to activation of HIF1α and induction of an overall mesenchymal phenotype with invadopodia and stress fibers (36). Another CLIC family member, CLIC3, in turn contributes to cell invasion through recycling of MT1-MMP and integrin α5β1 to the cell surface suggesting that stabilizing proteins involved in cell-extracellular matrix interactions is a common theme of CLIC family members (37, 38).…”

Section: Discussionmentioning

confidence: 99%

Relocation of CLIC1 Promotes Tumor Cell Invasion and Colonization of Fibrin

Gurski

Knowles

Basse

et al. 2015

Molecular Cancer Research

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Chloride intracellular channel 1 (CLIC1) has been shown to be up-regulated in various malignancies but its exact function remains unclear. Here, it is revealed that CLIC1 is critical for the stability of invadopodia in endothelial and tumor cells embedded in a 3-dimensional (3D) matrix of fibrin. Invadopodia stability was associated with the capacity of CLIC1 to induce stress fiber and fibronectin matrix formation following its β3 integrin (ITGB3)-mediated recruitment into invadopodia. This pathway, in turn, was relevant for fibrin colonization as well as slug (SNAI2) expression and correlated with a significant role of CLIC1 in metastasis in vivo. Mechanistically, a reduction of myosin light chain kinase (MYLK) in CLIC1- as well as β3 integrin-depleted cells suggests an important role of CLIC1 for integrin-mediated actomyosin dynamics in cells embedded in fibrin. Overall, these results indicate that CLIC1 is an important contributor to tumor invasion, metastasis and angiogenesis. Implications This study uncovers an important new function of CLIC1 in the regulation of cell-extracellular matrix interactions and ability of tumor cells to metastasize to distant organs.

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“…PULMONARY ARTERIAL HYPERTENSION (PAH) is a cardiopulmonary disease with a poor prognosis that is characterized by elevated pulmonary arterial pressure and leads to progressive right heart failure and ultimately death (57). Pharmacological agents moderately improve the patients' symptoms and the hemodynamic parameters of severe PAH, but none significantly reduces mortality (4,42).…”

mentioning

confidence: 99%

Suppression of endothelial PGC-1α is associated with hypoxia-induced endothelial dysfunction and provides a new therapeutic target in pulmonary arterial hypertension

Wang

et al. 2016

American Journal of Physiology-Lung Cellular and Molecular Phys

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Endothelial dysfunction plays a principal role in the pathogenesis of pulmonary arterial hypertension (PAH), which is a fatal disease with limited effective clinical treatments. Mitochondrial dysregulation and oxidative stress are involved in endothelial dysfunction. Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is a key regulator of cellular energy metabolism and a master regulator of mitochondrial biogenesis. However, the roles of PGC-1α in hypoxia-induced endothelial dysfunction are not completely understood. We hypothesized that hypoxia reduces PGC-1α expression and leads to endothelial dysfunction in hypoxia-induced PAH. We confirmed that hypoxia has a negative impact on endothelial PGC-1α in experimental PAH in vitro and in vivo. Hypoxia-induced PGC-1α inhibited the oxidative metabolism and mitochondrial function, whereas sustained PGC-1α decreased reactive oxygen species (ROS) formation, mitochondrial swelling, and NF-κB activation and increased ATP formation and endothelial nitric oxide synthase (eNOS) phosphorylation. Furthermore, hypoxia-induced changes in the mean pulmonary arterial pressure and right heart hypertrophy were nearly normal after intervention. These results suggest that PGC-1α is associated with endothelial function in hypoxia-induced PAH and that improved endothelial function is associated with improved cellular mitochondrial respiration, reduced inflammation and oxygen stress, and increased PGC-1α expression. Taken together, these findings indicate that PGC-1α may be a new therapeutic target in PAH.

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Aberrant Chloride Intracellular Channel 4 Expression Contributes to Endothelial Dysfunction in Pulmonary Arterial Hypertension

Cited by 62 publications

References 41 publications

Neutrophil Extracellular Traps Promote Angiogenesis

Neutrophil Extracellular Traps Promote Angiogenesis

Relocation of CLIC1 Promotes Tumor Cell Invasion and Colonization of Fibrin

Suppression of endothelial PGC-1α is associated with hypoxia-induced endothelial dysfunction and provides a new therapeutic target in pulmonary arterial hypertension

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