T-Helper 17 Cell Polarization in Pulmonary Arterial Hypertension

Hautefort, Aurélie; Girerd, Barbara; Montani, David; Cohen‐Kaminsky, Sylvia; Price, Laura; Lambrecht, Bart N.; Humbert, Marc; Perros, Frédèric

doi:10.1378/chest.14-1678

Cited by 84 publications

(79 citation statements)

References 44 publications

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“…31 This highlights the fact that KCNK3 inhibition acts on the whole spectrum of PAH pathomechanisms, from vasoconstriction and vascular cell proliferation to PAH-associated chronic inflammation. For instance and in accordance with our results, (1) TIMP-1 is overexpressed by cultured PASMCs from patients with iPAH, 32 and in vivo TIMP-1 gene transfer occurs in ratpotentialized PAH induced by chronic hypoxia 33 ; (2) MCP-1/ CCL2 is strongly involved in the development of human and experimental PAH 34,35 and plays a key role in arterial remodeling though direct mitotic/chemotactic effects on PASMCs and PAECs but also recruits monocytes/mononuclear cells and populations of circulating progenitors 36,37 ; and (3) there is an IL-17-dependent (Th17) immune polarization in PAH 38 and IL-17 mRNA, and protein expression is significantly increased in hypoxia-induced PH mouse models. 39 Interestingly, IL-17 binds to its receptor composed of IL-17RA and IL-17RC subtypes, leading to activation of the canonical ERK1/2, phosphoinositide 3-kinase-Akt, c-Jun N-terminal kinase, and p38 mitogen-activated protein kinase pathways.…”

Section: Discussionmentioning

confidence: 99%

Potassium Channel Subfamily K Member 3 (KCNK3) Contributes to the Development of Pulmonary Arterial Hypertension

et al. 2016

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P ulmonary artery (PA) hypertension (PAH) is a severe and progressive condition characterized by increased mean pulmonary arterial pressure >25 mm Hg at rest, with a normal PA wedge pressure in the absence of chronic respiratory, cardiac, or thromboembolic disease.1 PAH is a complex disease associated with endothelial cell (EC) dysfunction and Background-Mutations in the KCNK3 gene have been identified in some patients suffering from heritable pulmonary arterial hypertension (PAH). KCNK3 encodes an outward rectifier K + channel, and each identified mutation leads to a loss of function. However, the pathophysiological role of potassium channel subfamily K member 3 (KCNK3) in PAH is unclear. We hypothesized that loss of function of KCNK3 is a hallmark of idiopathic and heritable PAH and contributes to dysfunction of pulmonary artery smooth muscle cells and pulmonary artery endothelial cells, leading to pulmonary artery remodeling: consequently, restoring KCNK3 function could alleviate experimental pulmonary hypertension (PH). Methods and Results-We demonstrated that KCNK3 expression and function were reduced in human PAH and in monocrotaline-induced PH in rats. Using a patch-clamp technique in freshly isolated (not cultured) pulmonary artery smooth muscle cells and pulmonary artery endothelial cells, we found that KCNK3 current decreased progressively during the development of monocrotaline-induced PH and correlated with plasma-membrane depolarization. We demonstrated that KCNK3 modulated pulmonary arterial tone. Long-term inhibition of KCNK3 in rats induced distal neomuscularization and early hemodynamic signs of PH, which were related to exaggerated proliferation of pulmonary artery endothelial cells, pulmonary artery smooth muscle cell, adventitial fibroblasts, and pulmonary and systemic inflammation. Lastly, in vivo pharmacological activation of KCNK3 significantly reversed monocrotaline-induced PH in rats. Conclusions-In PAH and experimental PH, KCNK3 expression and activity are strongly reduced in pulmonary artery smooth muscle cells and endothelial cells. KCNK3 inhibition promoted increased proliferation, vasoconstriction, and inflammation. In vivo pharmacological activation of KCNK3 alleviated monocrotaline-induced PH, thus demonstrating that loss of KCNK3 is a key event in PAH pathogenesis and thus could be therapeutically targeted. (Circulation.

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Section: Discussionmentioning

confidence: 99%

Potassium Channel Subfamily K Member 3 (KCNK3) Contributes to the Development of Pulmonary Arterial Hypertension

et al. 2016

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“…45 Interestingly, although it is currently widely recognized that the T-helper 17 cells are crucial effectors of the autoimmune diseases, a T-helper 17 cell polarization has been recently demonstrated in PAH. 46 Because BET bromodomain inhibition has been shown to suppress T-helper 17-mediated pathology, 47 inhibition of autoimmune-mediated vascular injuries in PAH may be a point of therapeutic intervention by JQ1.…”

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confidence: 99%

Bromodomain-Containing Protein 4

Meloche

Potus

Vaillancourt

et al. 2015

Circulation Research

150

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P ulmonary arterial hypertension (PAH) is an obstructive vascular pathology affecting the small pulmonary arteries (PAs). It is characterized by enhanced inflammation, vasoconstriction, and proliferation/apoptosis imbalance within the artery wall, leading to increased pulmonary vascular resistance, right ventricular (RV) failure and death.1 PAH is a rare disease with an estimated prevalence of 15 to 50 cases/million 2 and its prevalence is thought to be highly underestimated [3][4][5][6] because of lack of symptom specificity. Despite recent therapeutic advances using vasodilator therapies, 1 most patients exhibit persistent poor exercise capacity and quality of life and their prognosis remains poor with a 3-year survival of 55% to 65%. 4,6,7 As in cancer, PAH is associated with sustained DNA damage, which accounts for a poly(ADP ribose) polymerase 1-dependent downregulation of and the activation of the nuclear factor of activated T cells (NFATs).8 The miR-204/NFAT axis affects mitochondrial function, bioenergetic profile and promotes the expression of oncogenes implicated in PAH, including B-cell lymphoma 2 (Bcl-2) and Survivin. 9,10 This results in the proproliferative and antiapoptotic phenotype of PAH pulmonary artery smooth muscle cells (PASMCs).

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“…In addition, circulating anti-endothelial cells and antifibroblast antibodies are found in 10-40% of patients suffering from idiopathic PAH [62][63][64][65], which may indicate the presence of autoimmune mechanisms linked to complement activation in the genesis of pulmonary vascular lesions of PAH. Consistently, altered regulatory T-cell function [66,67], T-helper 17 cell immune polarisation [68], dendritic cell recruitment in pulmonary vascular lesions [69] and the presence of lymphoid neogenesis in lungs have been demonstrated in patients with PAH [70,71]. However, the fact that steroid or aspirin treatment are clearly not effective in idiopathic and heritable PAH [72], and that prostacyclin, which has anti-inflammatory properties [73][74][75], does not reverse the pulmonary vascular remodelling and PAH, support the need for a better characterisation of the involvement and mechanism of distinct immune cells and key inflammatory mediators.…”

Section: Is Precision Medicine Ready For Use In Pah/ph?mentioning

confidence: 86%

Precision medicine and personalising therapy in pulmonary hypertension: seeing the light from the dawn of a new era

et al. 2018

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Pulmonary hypertension (PH) and pulmonary arterial hypertension (PAH) include different cardiopulmonary disorders in which the interaction of multiple genes with environmental and behavioural factors modulates the onset and the progression of these severe conditions. Although the development of therapeutic agents that modulate abnormalities in three major pathobiological pathways for PAH has revolutionised our approach to the treatment of PAH, the long-term survival rate remains unsatisfactory. Accumulating evidence has underlined that clinical outcomes and responses to therapy in PAH are modified by multiple factors, including genetic variations, which will be different for each individual. Since precision medicine, also known as stratified medicine or personalised medicine, aims to better target intervention to the individual while maximising benefit and minimising harm, it has significant potential advantages. This article aims to assemble and discuss the different initiatives that are currently underway in the PH/PAH fields together with the opportunities and prospects for their use in the near future.

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T-Helper 17 Cell Polarization in Pulmonary Arterial Hypertension

Cited by 84 publications

References 44 publications

Potassium Channel Subfamily K Member 3 (KCNK3) Contributes to the Development of Pulmonary Arterial Hypertension

Potassium Channel Subfamily K Member 3 (KCNK3) Contributes to the Development of Pulmonary Arterial Hypertension

Bromodomain-Containing Protein 4

Precision medicine and personalising therapy in pulmonary hypertension: seeing the light from the dawn of a new era

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