Bromodomain and extraterminal (BET) proteins have been suggested as a target for future pulmonary arterial hypertension (PAH) therapies, according to findings from a study published in the journal Respiratory Research.

Despite therapeutic advances for the treatment of PAH, the 3-year survival rate among patients is only approximately 70%. Although the use of pulmonary vasodilators, including endothelin receptor antagonists, prostacyclin analogs, and phosphodiesterase type V inhibitors, has been associated with improvements in morbidity and mortality rates, these agents are not curative.

It is well known that BET proteins are needed for expression of a subset of nuclear factor (NF)-κB-generated inflammatory genes that can be inhibited by the BET mimic JQ1+. The researchers hypothesized that BET mimics (eg, the BET small-molecule inhibitor JQ1+) would be effective in suppressing inflammation-driven functions of human pulmonary artery smooth muscle cells (HPASMCs) and human pulmonary microvascular endothelial cells (HPMECs) in patients with PAH. They examined the effect of JQ1+ on the regulation of tumor necrosis factor alpha (TNFα)-driven inflammatory responses in HPMECs and HPASMCs obtained from patients with PAH and non-PAH participants.

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Human peripheral lung tissue immunohistochemical staining for the BET proteins BRD2 and BRD4 was performed in 14 individuals with PAH and 12 non-PAH controls. In addition, HPASMCs and HPMECs from 4 individuals with PAH and 4 non-PAH controls were stimulated with TNFα in the presence or the absence of JQ1+ or its inactive isomer JQ1–. NF-κB p65 activation was established with use of a TransAM NF-κB p65 activation kit.

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Interleukin (IL)-6 and IL-8 mRNA was calculated via real-time quantitative polymerase chain reaction. Protein concentrations were measured with the use of enzyme-linked immunosorbent assays. MTT assays were used to assess cell viability.

Results of the study revealed that nuclear staining of BRD2 and BRD4 was increased significantly in the lung vascular HPMECs and HPASMCs derived from patients with PAH compared with the controls who exhibited normal pulmonary function (P< .0001). Further, TNFα-enhanced release of IL-6 from HPASMCs and HPMECs was greater in PAH cells than in non-PAH cells. Concentrations of CXCL8/IL-8 protein release were higher in PAH HPASMCs and HPMECs compared with non-PAH HPASMCs and HPMECs.

JQ1 had greater effectiveness on the release of CXCL8/IL-8 in HPASMCs and on release of IL-6 in HPMECs. Statistically significant increases in IL-6 were observed with TNFα levels of less than 1 ng/mL at 16 and 24 hours (P< .05), with cells from individuals with PAH releasing more IL-6 in response to TNFα compared with controls. Both the PAH and the non-PAH HPASMCs released 10-fold more IL-6 in response to TNFα than the PAH and the non-PAH HPMECs.

“In summary, our data show that JQ1 can suppress TNFα-stimulated inflammation by disrupting the recruitment of p65 and BRD4 to IL-6 and IL-8 promoters,” the researchers noted. “BET proteins could be a target for future therapies for [patients with] PAH,” they concluded.


Mumby S, Perros F, Grynblat J, et al. Differential responses of pulmonary vascular cells from PAH patients and controls to TNFα and the effect of the BET inhibitor JQ1. Respir Res. Published online July 29, 2023. doi:10.1186/s12931-023-02499-y