The role of the osteoprotegerin/tumor necrosis factor related apoptosis-inducing ligand axis in the pathogenesis of pulmonary arterial hypertension

AbstractTumor necrosis factor receptor-associated factor-interacting protein with a forkhead-associated domain (TIFA), a key regulator of inflammation, may be involved in the pathogenesis of pulmonary arterial hypertension (PAH). A total of 48 PAH patients (age 50.1 ± 13.1 years, 22.9% men), 25 hypertensive subjects, and 26 healthy controls were enrolled. TIFA protein expression in peripheral blood mononuclear cells (PBMCs) and plasma interleukin (IL)-1β and tumor necrosis factor (TNF)-α were measured. Pulmonary arterial hemodynamics were derived from right heart catheterization. PAH patients had the highest expression of TIFA, TNF-α, and IL-1β. TIFA protein expression was significantly associated with IL-1β (r = 0.94; P < 0.001), TNF-α (r = 0.93; P < 0.001), mean pulmonary artery pressure (r = 0.41; P = 0.006), and pulmonary vascular resistance (r = 0.41; P = 0.007). TIFA protein expression could independently predict the presence of PAH (odds ratio [95% confidence interval per-0.1 standard deviation]: 1.72 [1.37–2.16]; P < 0.001) and outperformed echocardiographic estimation. Ex vivo silencing of TIFA protein expression in PBMCs led to the suppression of the cellular expression of IL-1β and TNF-α. IL-1β and TNF-α mediated 80.4% and 56.6% of the causal relationship between TIFA and PAH, respectively, supporting the idea that TIFA protein is involved in the pathogenesis of PAH.

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TIFA Protein Expression is Associated with Pulmonary Arterial Hypertension

10.21203/rs.3.rs-149465/v1 ◽

2021 ◽

Author(s):

Hao-Chih Chang ◽

Tong-You Wade Wei ◽

Pei-Yu Wu ◽

Ming-Daw Tsai ◽

Wen-Chung Yu ◽

...

Keyword(s):

Pulmonary Arterial Hypertension ◽

Tumor Necrosis Factor ◽

Protein Expression ◽

Arterial Hypertension ◽

Tumor Necrosis ◽

Heart Catheterization ◽

Cellular Expression ◽

Tnf Α ◽

Pulmonary Arterial ◽

Necrosis Factor

Abstract Tumor necrosis factor receptor-associated factor-interacting protein with a forkhead-associated domain (TIFA), a key regulator of inflammation, may be involved in the pathogenesis of pulmonary arterial hypertension (PAH). A total of 48 PAH patients (age 50.1±13.1 years, 22.9% men), 25 hypertensive subjects, and 26 healthy controls were enrolled. TIFA protein expression in peripheral blood mononuclear cells (PBMCs) and plasma interleukin (IL)-1β and tumor necrosis factor (TNF)-α were measured. Pulmonary arterial hemodynamics were derived from right heart catheterization. PAH patients had the highest expression of TIFA, TNF-α, and IL-1β. TIFA protein expression was significantly associated with IL-1β (r=0.94; P<0.001), TNF-α (r=0.93; P<0.001), mean pulmonary artery pressure (r=0.41; P=0.006), and pulmonary vascular resistance (r=0.41; P=0.007). TIFA protein expression could independently predict the presence of PAH (odds ratio [95% confidence interval per-0.1 standard deviation]: 1.72 [1.37-2.16]; P<0.001) and outperformed echocardiographic estimation. Ex vivo silencing of TIFA protein expression in PBMCs led to the suppression of the cellular expression of IL-1β and TNF-α. IL-1β and TNF-α mediated 80.4% and 56.6% of the causal relationship between TIFA and PAH, respectively, supporting the idea that TIFA protein is involved in the pathogenesis of PAH.

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Tumor Necrosis Factor Induces Obliterative Pulmonary Vascular Disease in a Novel Model of Connective Tissue Disease–Associated Pulmonary Arterial Hypertension

Arthritis & Rheumatology ◽

10.1002/art.41309 ◽

2020 ◽

Vol 72 (10) ◽

pp. 1759-1770 ◽

Cited By ~ 1

Author(s):

Richard D. Bell ◽

R. James White ◽

Maria L. Garcia‐Hernandez ◽

Emily Wu ◽

Homaira Rahimi ◽

...

Keyword(s):

Pulmonary Arterial Hypertension ◽

Tumor Necrosis Factor ◽

Connective Tissue ◽

Arterial Hypertension ◽

Vascular Disease ◽

Tumor Necrosis ◽

Pulmonary Vascular Disease ◽

Pulmonary Arterial ◽

Novel Model ◽

Necrosis Factor

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Cytokines trigger disruption of endothelium barrier function and p38 MAP kinase activation in BMPR2-silenced human lung microvascular endothelial cells

Pulmonary Circulation ◽

10.1177/2045894019883607 ◽

2019 ◽

Vol 9 (4) ◽

pp. 204589401988360 ◽

Cited By ~ 3

Author(s):

Birger Tielemans ◽

Leanda Stoian ◽

Rik Gijsbers ◽

Annelies Michiels ◽

Allard Wagenaar ◽

...

Keyword(s):

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Barrier Function ◽

Tumor Necrosis ◽

Tumor Necrosis Factor Α ◽

Endothelial Barrier ◽

Endothelial Barrier Function ◽

Pulmonary Arterial ◽

Factor Α ◽

Necrosis Factor

The bone morphogenetic protein receptor II (BMPRII) signaling pathway is impaired in pulmonary arterial hypertension and mutations in the BMPR2 gene have been observed in both heritable and idiopathic pulmonary arterial hypertension. However, all BMPR2 mutation carriers do not develop pulmonary arterial hypertension, and inflammation could trigger the development of the disease in BMPR2 mutation carriers. Circulating levels and/or lung tissue expression of cytokines such as tumor necrosis factor-α or interleukin-18 are elevated in patients with pulmonary arterial hypertension and could be involved in the pathogenesis of pulmonary arterial hypertension. We consequently hypothesized that cytokines could trigger endothelial dysfunction in addition to impaired BMPRII signaling. Our aim was to determine whether impairment of BMPRII signaling might affect endothelium barrier function and adhesiveness to monocytes, in response to cytokines. BMPR2 was silenced in human lung microvascular endothelial cells (HLMVECs) using lentiviral vectors encoding microRNA-based hairpins. Effects of tumor necrosis factor-α and interleukin-18 on HLMVEC adhesiveness to the human monocyte cell line THP-1, adhesion molecule expression, endothelial barrier function and activation of P38MAPK were investigated in vitro. Stable BMPR2 silencing in HLMVECs resulted in impaired endothelial barrier function and constitutive activation of P38MAPK. Adhesiveness of BMPR2-silenced HLMVECs to THP-1 cells was enhanced by tumor necrosis factor-α and interleukin-18 through ICAM-1 adhesion molecule. Interestingly, tumor necrosis factor-α induced activation of P38MAPK and disrupted endothelial barrier function in BMPR2-silenced HLMVECs. Altogether, our findings showed that stable BMPR2 silencing resulted in impaired endothelial barrier function and activation of P38MAPK in HLMVECs. In BMPR2-silenced HLMVECs, cytokines enhanced adhesiveness capacities, activation of P38MAPK and impaired endothelial barrier function suggesting that cytokines could trigger the development of pulmonary arterial hypertension in a context of impaired BMPRII signaling pathway.

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