There has also been little progress in identifying and preventing PH in those at risk for the disease. A new study published in EMBO Molecular Medicine by researchers from Brigham and Women’s Hospital (BWH) sheds light on the disease’s surprising cause, with crucial implications for diagnosis, treatment, and prevention of PH in persons at risk.
“We’ve identified a cause for the disease that may help us identify new populations most in danger of developing pulmonary hypertension,” said Stephen Chan, MD, PhD, a physician-scientist in the Division of Cardiovascular Medicine of BWH and senior author of the study. “Our findings help us better understand how this disease initiates and should help us develop much better drugs for treatment and perhaps, someday, a cure.”
In studies that have spanned nearly eight years of work, Chan and his colleagues found that specific disruptions in mitochondria, the powerhouses of cells, lead to alterations of energy production, or metabolism, of blood vessels of the lungs. ISCU is a critical human protein that generates factors called iron-sulfur clusters essential for normal mitochondrial function. In a mouse model of the disease, the team found that microRNAs – small loops of genetic material – tamp down ISCU. This can then incite catastrophic molecular consequences culminating in PH.
Based on their findings in animal models, Chan’s team went on to study a 29 year old woman with two defective copies of the ISCU gene. At rest, the woman’s blood pressure and heart function appeared relatively normal, but exercise testing revealed unambiguous dysfunction of blood vessels in her lung. Importantly, the patient improved when placed on a PH drug to relax and widen the smooth muscle lining her lung blood vessels.
“This is the first known observation of pulmonary vascular dysfunction in a person with ISCU deficiency,” Chan explained. “Her case helps draw a definitive connection between ISCU and PH. Perhaps even more exciting is that we were able to catch her disease and treat it at an early stage. We hope this will prevent or at least slow down the progression over time.”
Identifying patients with mutations in other genes that contribute to iron-sulfur deficiencies early could give clinicians the ability to intervene before a patient develops PH. The new study also highlights the possibility of designing new drugs to treat PH that focus on ISCU proteins, the microRNA that targets them, and other genes known to be directly linked to iron biology in general but have yet to be studied in PH. Finally, Chan’s team predicts that there likely exist a number of additional medical conditions ranging from heart disease, cancer, and neurologic disease that may share a dependence on iron-sulfur generation and could be treated similarly.
“There is still a lot of work to be done,” said Chan. “But, we feel this represents a major advance in our efforts to fight this disease.”
This work was supported by the NIH (K08HL096834; U54-CA151884, R01-DE016516-06, and EB000244); the McArthur-Radovsky, Lerner, Harris, and Watkins Funds; Gilead Research Scholars Fund; the Pulmonary Hypertension Association; and the Intramural Research Program of the National Human Genome Research Institute.
Brigham and Women’s Hospital