DKK1 activated the NF-κB pathway by binding with CKAP4 to induce PASMC oxidative stress and promote pulmonary arterial hypertension.

BACKGROUND

Pulmonary arterial hypertension (PAH) is a hemodynamic disorder that can progress to right heart failure and result in death.

OBJECTIVE

This study investigated the molecular mechanisms underlying the onset and progression of PAH to identify potential therapeutic targets.

METHODS

Peripheral blood samples from PAH patients were analyzed to assess serum levels of DKK1 and CKAP4, as well as NF-κB pathway activation. Supernatants from hypoxia-treated pulmonary artery endothelial cells (PAECs), plasmid-transfected cells, and SC75741-treated cells were used to modulate pulmonary artery smooth muscle cells (PASMCs). RT-qPCR, Western blot, and ELISA were employed to quantify DKK1 and CKAP4 expression and evaluate NF-κB pathway activation in PASMCs. EdU staining and CCK-8 viability assay were performed to assess cell proliferation, while DCFH-DA staining and ELISA were used to measure ROS, SOD, and MDA levels.

RESULTS

DKK1 and CKAP4 expression were positively correlated, and both were upregulated with increasing pulmonary artery systolic pressure (PASP) in PAH patients. The supernatant from hypoxia-exposed PAECs induced NF-κB pathway activation, cell proliferation, and oxidative stress in PASMCs, effects that were inhibited by siDKK1, siCKAP4, and SC75741.

CONCLUSIONS

Hypoxia stimulated PAECs to secrete DKK1, which in turn upregulated CKAP4 expression and activated the NF-κB pathway in PASMCs, promoting cell proliferation and oxidative stress.