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 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 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 paper, The zinc transporter ZIP12 regulates the pulmonary vascular
response to chronic hypoxia, is published inNature.