The role of nuclear factor of activated T cells in pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is characterized by enhanced proliferation and reduced apoptosis of pulmonary artery smooth muscle cells (PASMCs). Because microRNAs have been recently implicated in the regulation of cell proliferation and apoptosis, we hypothesized that these regulatory molecules might be implicated in the etiology of PAH. In this study, we show that miR-204 expression in PASMCs is down-regulated in both human and rodent PAH. miR-204 down-regulation correlates with PAH severity and accounts for the proliferative and antiapoptotic phenotypes of PAH-PASMCs. STAT3 activation suppresses miR-204 expression, and miR-204 directly targets SHP2 expression, thereby SHP2 up-regulation, by miR-204 down-regulation, activates the Src kinase and nuclear factor of activated T cells (NFAT). STAT3 also directly induces NFATc2 expression. NFAT and SHP2 were needed to sustain PAH-PASMC proliferation and resistance to apoptosis. Finally, delivery of synthetic miR-204 to the lungs of animals with PAH significantly reduced disease severity. This study uncovers a new regulatory pathway involving miR-204 that is critical to the etiology of PAH and indicates that reestablishing miR-204 expression should be explored as a potential new therapy for this disease.

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The Role of Regulatory T Cells in Pulmonary Arterial Hypertension

Frontiers in Immunology ◽

10.3389/fimmu.2021.684657 ◽

2021 ◽

Vol 12 ◽

Author(s):

Wen Tian ◽

Shirley Y. Jiang ◽

Xinguo Jiang ◽

Rasa Tamosiuniene ◽

Dongeon Kim ◽

...

Keyword(s):

T Cells ◽

Pulmonary Arterial Hypertension ◽

Regulatory T Cells ◽

Arterial Hypertension ◽

Right Heart Failure ◽

Strongly Correlated ◽

Incurable Condition ◽

Pulmonary Arterial ◽

Inflammatory Milieu

Pulmonary arterial hypertension (PAH) is a chronic, incurable condition characterized by pulmonary vascular remodeling, perivascular inflammation, and right heart failure. Regulatory T cells (Tregs) stave off autoimmunity, and there is increasing evidence for their compromised activity in the inflammatory milieu of PAH. Abnormal Treg function is strongly correlated with a predisposition to PAH in animals and patients. Athymic Treg-depleted rats treated with SU5416, an agent causing pulmonary vascular injury, develop PAH, which is prevented by infusing missing CD4+CD25highFOXP3+ Tregs. Abnormal Treg activity may also explain why PAH disproportionately affects women more than men. This mini review focuses on the role of Tregs in PAH with a special view to sexual dimorphism and the future promise of Treg therapy.

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A Primary Role of Activated CD8+ T-Cells in the Pathogenesis of Pulmonary Arterial Hypertension.

10.1164/ajrccm-conference.2009.179.1_meetingabstracts.a2360 ◽

2009 ◽

Author(s):

G Sutendra ◽

S Bonnet ◽

P Dromparis ◽

S McMurtry ◽

A Haromy ◽

...

Keyword(s):

T Cells ◽

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Cd8 T Cells ◽

Primary Role ◽

Pulmonary Arterial

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Navigating the Road to Transplant in Pulmonary Arterial Hypertension: A Road Less Taken

Advances in Pulmonary Hypertension ◽

10.21693/1933-088x.15.1.12 ◽

2016 ◽

Vol 15 (1) ◽

pp. 12-13

Author(s):

Adaani E. Frost ◽

Harrison W. Farber

Keyword(s):

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Lung Transplantation ◽

Small Cell ◽

Small Cell Lung ◽

Donor Organ ◽

The Road ◽

Lung Allocation Score ◽

Pulmonary Arterial

Dramatic advances in therapy for pulmonary arterial hypertension (PAH) in the last 20 years have improved survival from a median of 2.5 years in the pretreatment era to 7.5 years currently. However, impressive as that may seem, it is important to note that a median survival of 7.5 years is equivalent to that of surgically resected non-small cell lung cancer, thus underscoring the importance of lung transplantation as a treatment option in patients with PAH. In this edition of Advances, Edelman has reviewed the pathway to transplantation for patients with PAH, detailing the recommendations for timing of referral, listing for lung transplantation, the role of the lung allocation score in allocating a donor organ, and the outcome of lung transplantation.

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