Research By Rashmi Hegde, PhD
Post Date: September 12, 2019 | Publish Date: Sept. 12, 2019
Scientists have identified a molecular pathway that contributes to the development of pulmonary arterial hypertension (PAH), a severe, often fatal condition that has no cure.
The discovery, published Sept. 12, 2019, in Nature Communications, suggests a new target for developing new drug therapies for PAH, according to researchers at Cincinnati Children’s Hospital Medical Center.
This progressive disease is characterized by high blood pressure in the lungs, and affects adults and children. When left untreated, PAH can lead to fatal heart damage.
Scientists have long known that a process called vascular remodeling drives the thickening of lung arteries that contributes to the increased pressure. Reversing vascular remodeling could be curative.
“PAH is a life-threatening disease in adults and can also complicate the repair of congenital heart disease in children,” says lead study investigator Rashmi Hegde, PhD, Division of Developmental Biology. “While progress is being made to develop treatments, there currently is no effective cure available. The new molecular pathway described by our study could be targeted to develop effective therapeutics for the disease.”
The current study describes a molecular pathway involving the protein Eyes Absent 3 (EYA3). This protein promotes vascular remodeling and could be targeted in the development of PAH therapeutics, Hegde says. EYA proteins have a mechanistically unique enzyme activity first identified by Hedge and her colleagues in 2003.
In this study, the research team manipulated transgenic mice with CRISPR gene editing technology to inactivate EYA3, which significantly protected the lung arteries from vascular remodeling. When researchers tested pharmacological inhibition with previously identified drugs that target the EYA3 pathway, significant reversal of vascular remodeling was seen in laboratory rat models.
Additional research is needed before a treatment strategy could be available for human testing. Beyond existing medications that target EYA3, the researchers want to design a treatment that even more precisely targets remodeling in PAH.
Major contributors to this study were first author Yuhua Wang, PhD, and Ram Naresh Pandey, MS, both researchers in Hegde’s laboratory.
Funding support was provided by the National Institutes of Health (NIH-NCAI-14-2-APP-CCHMC-Hegde and NCI RO1-CA207068) and Cincinnati Children’s. The study involved extensive collaboration between scientists in Developmental Biology, Pulmonary Biology, the Cincinnati Children’s Heart Institute, Human Genetics, and the Cincinnati Children’s Perinatal Institute.
|Original Title:||The EYA3 tyrosine phosphatase activity promotes pulmonary vascular remodeling in pulmonary arterial hypertension|
|Published in:||Nature Communications|
|Publish date:||Sept. 12, 2019|
The Research Horizons blog features news and insights about the latest discoveries and innovations developed by the scientists of Cincinnati Children's. This blog does not provide medical advice, diagnosis, or treatment.