Pulmonary arterial hypertension (PAH) is a progressive, debilitating disease characterised by increased resistance in pulmonary arteries, placing additional workload on the right ventricle of the heart. Untreated, the disease frequently results in right ventricular failure and death. Until the 1990s the only effective treatment was heart-lung transplantation. Subsequently, drug treatments that have been used include anticoagulants, calcium channel blockers, prostacylin and endothelin receptor antagonists. Whilst these drugs have demonstrated efficacy in PAH patients, delaying the need for lung transplantation, long term survival rates have not been significantly impacted.
The annual incidence of PAH is around 1-2 per million individuals, with a further 8 per million contributed by PAH associated with scleroderma. Despite the low incidence, there are approximately 100,000 PAH patients in Europe and the US.
Scientists at University of California–San Diego (UCSD) have now established that human pulmonary hypertension is characterised by overexpression of Notch3 in small pulmonary artery smooth muscle cells and that the severity of disease in humans and rodents correlates with the amount of Notch3 protein in the lung. In the study, published online in Nature Medicine on 25th October, the team showed that mice with homozygous deletion of Notch3 do not develop pulmonary hypertension in response to hypoxic stimulation. Additionally, mice with pulmonary hypertension were successfully treated with a DAPT, a γ-secretase inhibitor that blocks activation of Notch3.
Notch receptor signalling is implicated in control of smooth muscle cell proliferation and maintaining smooth muscle cells in an undifferentiated state. The discovery that the Notch3 signalling pathway is crucial for the development of PAH provides a novel target for therapeutic intervention.