Targeting AURKB enzyme a promising approach in PAH rats
Results show improvements in measures of blood flow
Inhibiting an enzyme known as Aurora kinase B (AURKB) significantly improves multiple measures of blood flow in rat models of pulmonary arterial hypertension (PAH), a study suggests.
AURKB blockade worked by suppressing the excessive growth of blood vessel muscle cells, which contributes to the narrowing of pulmonary arteries that drive elevated blood pressure in PAH. The study, “Unraveling AURKB as a potential therapeutic target in pulmonary hypertension using integrated transcriptomic analysis and pre-clinical studies,” was published in Cell Reports Medicine.
Pulmonary artery smooth muscle cells, or PASMCs, are specialized muscle cells within the walls of pulmonary arteries, which are the blood vessels that pass through the lungs. They regulate blood flow by contracting and relaxing to adjust the arteries’ diameter.
In PAH, the excessive growth of PASMCs, along with endothelial cells, which line the inside of blood vessels on top of PASMCs, contributes to vascular remodeling, a process that narrows the pulmonary arteries, restricts blood flow, and drives up blood pressure, causing symptoms.
Most standard PAH treatments are intended to relax and widen arteries to improve blood flow, lower blood pressure, and ease symptoms. Recently, Winrevair (sotatercept-csrk) was approved to boost functional abilities in PAH by addressing abnormal endothelial cell growth.
However, “none of these therapies offers a cure, justifying continued efforts to unravel the molecular mechanisms underlying PAH and to identify new targets specifically involved in the remodeling process,” the researchers wrote.
Inhibiting the AURKB enzyme
To identify the underlying molecular processes driving vascular remodeling in PAH, a research team in Canada, Germany, and the U.S. compared the gene expression (activity) signatures of PASMCs from PAH patients and healthy people.
The activity of the AURKB gene was significantly increased in PASMCs from PAH patients compared with healthy people and in cells isolated from rats with induced PAH. Consistent with these findings, the levels of the AURKB enzyme encoded by the gene were significantly higher in PASMCs from patients.
AURKB’s role in PAH was confirmed when PASMCs were exposed to barasertib — a molecule that selectively inhibits the enzyme — which suppressed cell proliferation and reversed the abnormal gene signature in PAH PASMCs. Further experiments showed that inhibiting AURKB promoted PASMC apoptosis, a type of programmed cell death, or cellular senescence, when cells no longer divide, but remain alive and active.
To determine if blocking the enzyme might treat PAH patients, the researchers examined the effects of barasertib in male rats with chemically induced PAH.
Barasertib significantly improved PAH-related measures of blood flow. This included reduced blood pressure in the pulmonary arteries and the heart’s right ventricle during a heartbeat and a drop in resistance to pulmonary blood flow. Right ventricular hypertrophy, when the right side of the heart becomes enlarged in response to pulmonary hypertension, was also significantly decreased. Barasertib’s benefits in blood flow were also observed in rats with PAH induced chemically combined with a lack of oxygen.
Moreover, when thin slices of human lung tissue were exposed to a cocktail of growth factors to induce vascular remodeling, barasertib treatment attenuated the growth factor-stimulated thickening of the pulmonary arteries.
The researchers noted that cellular senescence is a common outcome of anti-remodeling drugs that may be “detrimental in the middle/long term.” Therefore, they tested a combination of barasertib and UC2288, a drug that targets and clears senescent cells. While UC2288 alone didn’t reverse pulmonary hypertension in either PAH rat model, when it was combined with barasertib, measures of blood flow were significantly improved beyond that of barasertib alone.
“Our studies provide evidence that AURKB promotes PASMC proliferation and pulmonary vascular remodeling in PAH,” the researchers wrote. “Although our results support the concept of a combination treatment that leverages both AURKB and senescence to therapeutic ends, the optimal approach remains to be defined.”
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