Inflammatory TIFA Protein Elevated in PAH

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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TIFA Protein in PAH

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A protein called TIFA is elevated in the blood cells of people with pulmonary arterial hypertension (PAH), suggesting this protein is involved in the biological processes that drive the disease, according to a new study.

The findings were published in the journal Scientific Reports, in the study, “TIFA protein expression is associated with pulmonary arterial hypertension.”

TIFA — short for tumor necrosis factor receptor-associated factor-interacting protein with a forkhead-associated domain — is a protein that helps to regulate inflammation. Prior research has indicated that several other inflammation-mediating proteins are present at higher-than-normal levels in PAH, implying these inflammatory proteins are involved in the disease. However, the role of TIFA in PAH has not been clear.

In the new study, researchers in Taiwan assessed TIFA levels in the blood cells of 48 people with PAH (mean age 50.1 years), including 32 with idiopathic (no known cause) PAH and 16 with connective tissue disease-associated PAH (CTD-PAH). For comparison, the researchers also assessed 25 people with systemic hypertension, or high blood pressure, and 26 people with no known health issues (controls).

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Statistical analyses showed that TIFA levels were significantly higher in people with PAH than in those with systemic hypertension. In addition, TIFA levels were higher in people with systemic hypertension than in controls.

Among the PAH group, TIFA levels were significantly higher among those with CTD-PAH than idiopathic disease.

“The differences in TIFA protein expression observed in our study indicate a spectrum of varying degrees of inflammation in different etiologies [causes] of PAH,” the researchers wrote.

Levels of other inflammatory proteins in the blood — namely interleukin 1-beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha), both of which have been linked with the development of PAH — followed generally similar trends to TIFA levels. Statistical analyses showed significant correlations between levels of these proteins and TIFA, meaning individuals with high TIFA levels were statistically likely to have high levels of IL-1beta and TNF-alpha.

Among people with PAH, TIFA levels correlated with estimated right ventricular systolic pressure (eRVSP), showing that PAH patients with higher TIFA levels tended to have higher blood pressure in the artery going from the heart to the lungs.

“To the best of our knowledge, this study is the first to demonstrate TIFA protein overexpression in [blood cells] of PAH patients and the significant association between TIFA protein expression and plasma levels of [IL-1beta and TNF-alpa],” the researchers wrote.

Further analyses indicated that measuring TIFA levels could be used to distinguish between individuals with or without PAH. TIFA levels could predict PAH diagnosis with a sensitivity (true-positive rate) of 100%, and a specificity (true-negative rate) of 90.2%.

Experiments using cells in dishes demonstrated that decreasing levels of TIFA led to decreased production of IL-1beta and TNF-alpha. This indicates that TIFA “may contribute to the development of PAH” by activating these inflammatory proteins, which may be a useful starting point for future studies, according to the researchers.

“It is worth exploring the mechanisms of how TIFA initiates the progression of PAH and systemic hypertension and the feasibility of TIFA as a novel therapeutic target in future studies,” the team concluded.

The researchers noted this study is limited by its relatively small sample size, so more research is needed to validate these results. They also acknowledged that TIFA’s role may not be specific to PAH, with its elevated levels possibly resulting from underlying autoimmune diseases.