Researchers identify new drug target for serious heart and lung condition

A gene has been identified that sheds new light on a potentially fatal heart and lung condition and could lead to a new treatment.

The findings, published today in Nature, indicate that a new treatment for pulmonary arterial hypertension (PAH), a debilitating disease, could be produced by suppressing this gene.

Pulmonary hypertension occurs when blood vessels in the lung constrict and become stiffer, putting a strain on the heart as it tries to pump blood through the lungs. It can be brought on at high altitudes due to a lack of oxygen in the air, but there are also more severe forms of the condition, including PAH, with around 6,500 people diagnosed with PAH in the UK in total.

PAH is chronic and debilitating and leads to heart failure. PAH leaves sufferers feeling breathless and exhausted. Current treatments target only the symptoms and prognosis is very poor. Once diagnosed with PAH, a person has a 30 per cent chance of dying within three years.

The research team, led by Professor Martin Wilkins and Dr Lan Zhao from the Department of Medicine at Imperial College London, have identified a gene that is switched on in the blood vessels of the lung in pulmonary hypertension. Disabling this gene helps protect against pulmonary hypertension in low oxygen conditions. The team believe this provides a clue for a new treatment approach to PAH.

The gene was first identified in a type of rat that is resistant to developing pulmonary hypertension in a low oxygen atmosphere. It is responsible for producing a protein called ZIP12, which regulates zinc levels in cells. It is not active in normal lungs but is switched on in the lungs of people with PAH and other types of pulmonary hypertension.

Specialists from the Medical Research Council's Clinical Sciences Centre (CSC) helped to generate the rats in which the important transporter ZIP12 was missing. This was critical in identifying the gene that was important, and is the first time that rats of this kind have been generated at Imperial College.

Treatments currently available for PAH can offer some relief but they do not tackle the cause of the disease. By developing drugs that can act on the ZIP12 protein it may now be possible to reverse or delay the progression of the disease. These drugs may also provide protection against PAH in people at risk.

Professor Martin Wilkins said: “Very little is known about the link between zinc transporters and cardiovascular disease. With this research we show that a gene involved in the way that zinc is transported within our cells is also involved in a chronic illness called pulmonary arterial hypertension. Our research provides a new opportunity to understand how pulmonary hypertension develops, and with this find new ways to treat this illness.”

Dr Lan Zhao said: "This finding has important implications for people and animals living at high altitude where oxygen levels are low. Over 140 million people live above 2500m. It will help us understand why some people are more likely than others to develop pulmonary hypertension, and to develop new ways to tackle the condition.”

Professor Amanda Fisher, director of the CSC said: "What is exciting about this work is that it clearly demonstrates how much can be achieved by working together on a scientific problem, and heralds the prospect of further collaborations of this kind between CSC specialists and teams from Imperial College."

Professor Jeremy Pearson, Associate Medical Director at the BHF, said: “Pulmonary arterial hypertension (PAH), though uncommon, leads to substantially reduced quality of life and reduced life expectancy. It is currently incurable and new drugs are urgently needed to improve treatment. Professor Wilkins’ group has found completely unexpectedly that a gene regulating zinc uptake into cells controls the development of pulmonary hypertension when oxygen levels are low, that the same gene is switched on in the lungs of people suffering from PAH, and that blocking it can protect rats from the disease. These exciting findings hold out the hope of designing completely novel drugs to tackle this serious disease.”

The research was funded by the British Heart Foundation, the Wellcome Trust, the Medical Research Council and the Royal Society.