Suppressing NEK2 may reverse vascular remodeling in PAH: Study
Rat study finds reducing protein lessens changes in heart, blood vessels
Reducing the levels of the protein NEK2 in the pulmonary arteries lessened disease-driving changes in blood vessels and the heart of a rat model of pulmonary arterial hypertension (PAH) due to congenital heart disease (CHD).
The effects were tied to a modulation of the NF-kB pathway involved in vascular remodeling, a set of changes in blood vessels’ arrangement and structure that underlies PAH, the study found.
“Targeting NEK2 may be an effective strategy for the treatment of CHD-PAH,” the investigators wrote.
The study, “NEK2 inhibition reverses vascular remodeling in pulmonary arterial hypertension associated with congenital heart disease,” was published in Cellular Signalling.
PAH is characterized by the narrowing of pulmonary arteries, the small blood vessels that carry blood through the lungs, restricting blood flow across the lungs and leading to high blood pressure, or hypertension, and making the heart work harder to pump blood. This can cause enlargement of the right heart ventricle and lead to heart failure later in life.
Vascular remodeling
Pulmonary vascular remodeling underlies blood vessel narrowing and is marked by the proliferation of smooth muscle cells (PASMCs) in the arterial wall. PAH can be associated with congenital heart disease, which involves problems with heart structure or function that are present at birth.
NEK2 is known to play a role in cancer proliferation by activating the NF-kB signaling pathway, which is involved in PAH development. However, the “functional importance of NEK2 in PAH associated with CHD (CHD-PAH) has not been elucidated yet,” the researchers wrote.
To learn more, the team in China analyzed the levels of NEK2, and its relation with pulmonary vascular remodeling, in PASMCs derived from people with CHD-PAH and in a rat model of the disease.
Human cells were obtained from 22 lung tissue samples from patients who underwent right heart catheterization, a procedure used to diagnose PAH. NEK2 levels were found to be increased, or overexpressed, in patients’ PASMCs, particularly in samples from patients with irreversible PAH (mean pulmonary arterial pressure of at least 25 mmHg).
Similar results were observed in PASMSCs derived from a PAH rat model.
To further understand how NEK2 may contribute to PASMC dysfunction in PAH, patient-derived cells were engineered in the lab to express higher or lower levels of the protein. When NEK2 was overexpressed, there was also an increase in markers of cell growth, migration, and cell death resistance, while a decrease in NEK2 levels produced the opposite results.
“Taken together, these results suggest that upregulation of NEK2 promotes the proliferation, migration, and apoptosis resistance of [human] PASMCs, which may contribute to pulmonary vascular remodeling,” the researchers wrote. Apoptosis refers to programmed cell death, which differs from cell death caused by injury.
The activation of the NF-κB pathway increased when NEK2 was overexpressed, and reduced with decreased levels of the protein, suggesting “that NEK2 may contribute to [human] PASMC dysfunction via the NF-κB pathway,” the researchers wrote.
They tested whether suppressing NEK2 expression may be an effective strategy for reversing PAH. For that, they used adeno-associated viruses, a commonly used gene delivery vehicle, administered into the windpipe.
In the PAH rats, results showed significantly higher blood vessel wall thickness, as well as higher blood pressure in the pulmonary arteries and enlarged right heart ventricles. Suppressing NEK2 production lessened these PAH-related changes.
“Our findings provide further insights into the maladaptive arterial remodeling of CHD-PAH, and highlight the potential of NEK2 as a putative therapeutic target for pulmonary vascular remodeling,” the researchers wrote.
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