Study Identifies New Drug Target for Pulmonary Arterial Hypertension

Study Identifies New Drug Target for Pulmonary Arterial Hypertension

Recently, a group of researchers from the Imperial College of London released study results in which they identified a gene that could lead to future efficacious treatment options for patients with pulmonary arterial hypertension (PAH).  The study, entitled “The zinc transporter ZIP12 regulates the pulmonary vascular response to chronic hypoxia” was published in the latest edition of the journal Nature.

Pulmonary Arterial Hypertension

PAH, also known as pulmonary hypertension, defines a group of debilitating idiopathic (of unknown origin) or co-morbid conditions that cause breathlessness, loss of exercise capacity, and death due to elevated pulmonary artery pressure and subsequent right side heart failure. It is a rare condition affecting 1 to 2 individuals for every 1 million in the US and Europe.  According to the CDC, PAH is more common among women, non-Hispanic blacks, and individuals 75 years or older.

PAH is characterized by high blood pressure (BP) in the pulmonary arteries, which carry oxygen and blood from the heart to the lungs.  In healthy individuals, pulmonary arterial pressure should be approximately 25/10 millimeters of mercury (mmHg); for patients diagnosed with PAH this pressure consistently exceeds 40/20 mmHg. This elevated arterial pressure causes the right ventricle of the heart, which supplies blood to the pulmonary arteries, to pump ineffectively. This results in the right side of the heart working harder to pump blood around the body, leading to the condition’s debilitating effects and the eventual pre-mature death of the patient. PAH is most often inadvertently discovered after a patient undergoes echocardiography or right heart catheterization for another condition; as a result, it is generally not diagnosed until the disease is advanced and the right side of the heart begins to fail.

About This Study

In this study, which was funded by the British Heart Foundation, the Wellcome Trust, the Medical Research Council and the Royal Society, the investigators used an experimental rat model missing Slc39a12, a gene responsible for producing a protein called ZIP12, which regulates zinc levels in cells and normal disease free rat models, then compared the rate of PAH. Their findings confirmed that the Slc39a12 gene played a major role in disease onset in this animal model.

In a University press release about the study, Dr. Martin Wilkins, Professor of Clinical Pharmacology, Head of the Division of Experimental Medicine, ICL, Director of the National Institute of Health Research Wellcome Trust Imperial Clinical Research Facility, and senior study author, stated, “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. Wilkins’ colleague and lead study author Dr Lan Zhao, Professor of Medicine and Principal Investigator in the Cardiovascular Group, ICL, shared his enthusiasm over the findings: “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.”

The current treatment options offer relief to patients suffering with PAH, but not a cure.  The researchers believe that the long-term implications of their findings could include the development of drugs that can act specifically on the ZIP12 protein making it possible to reverse or delay the progression of the disease.

For Professor Amanda Fisher, director of the Medical Research Council’s Clinical Sciences Centre, ICL, noted that “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.”

Dr, Fischer’s colleague Professor Jeremy Pearson, Associate Medical Director at the British Heart Foundation, shared in her excitement: “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.”

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