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Scientists Discover Potential New Treatment For Pulmonary Hypertension

Researchers at Indiana University and Notre Dame have discovered a potential new treatment for pulmonary hypertension, focusing on reversing vascular remodeling through an epigenetic pathway involving the protein SPHK2, as reported in Circulation Research. This innovative approach could transform the treatment of this serious lung condition.

Researchers at the Indiana University School of Medicine, at the school's South Bend regional campus, and their colleagues at the University of Notre Dame, have discovered a novel therapeutic target for treating pulmonary hypertension. This form of high blood pressure specifically impacts the blood vessels in the lungs. The team's research and findings have been recently published in the journal Circulation Research.

Pulmonary hypertension is a complex and often fatal condition that makes the heart work harder than normal to pump blood into the lungs. While the exact causes of pulmonary hypertension are unknown, one of its hallmarks is the thickening of the pulmonary blood vessels caused by an overgrowth of cells, also known as vascular remodeling.

New Therapeutic Discoveries

Margaret A. Schwarz, MD, a professor of pediatrics at IU School of Medicine and senior author on the study, said there are few treatments for pulmonary hypertension, and they typically treat the symptoms of vascular remodeling rather than the remodeling itself.

Schwarz said what's exciting about her team's findings is the discovery of an epigenetic pathway mediated via the protein SPHK2 that can reduce and potentially reverse vascular remodeling in pulmonary hypertension.

Dushani Ranasinghe, PhD, left, and Margaret Schwarz, MD, at Ranasinghe's graduation ceremony from the University of Notre Dame. Credit: Courtesy of Margaret Schwarz

"This is one of the very first mechanisms of pulmonary hypertension identified that can be reversible," she said. "Normally, pulmonary hypertension patients are given medications to reduce the vascular pressure in the lungs or to help the heart squeeze better to pump blood, which are both symptoms of vascular remodeling. Our study looks at targeting the epigenetic reversal of this mechanism. Ultimately, the treatment would be to stop the vascular remodeling process entirely."

The concept is similar to cancer treatment, Schwarz said.

"In cancer, we stop tumor growth instead of just treating symptoms," she said. "Vascular remodeling is a different mechanism, but the idea is that the treatment would target the mechanism instead of the symptoms."

Key Findings and Future Directions

Other key findings from the study include:

SPHK2 can drive pulmonary hypertension pathogenesis via histone H3K9 hyperacetylation, contributing to pulmonary artery smooth muscle cell (PASMC) vascular remodeling.

SPHK2 deficiency confers reduced pulmonary vascular resistance, right ventricle hypertension, and distal vessel wall thickness.

EMAP (endothelial monocyte activating polypeptide) II has a key role in the stimulation of nuclear SPHK2/S1P epigenetic modulating axis, suggesting that cooperation between SPHK2 and

EMAPII could be a major driving force for epigenetic-mediated vascular PASMC reprogramming and remodeling in pulmonary hypertension.

Pulmonary vascular endothelial cells are a priming factor of the EMAPII/SPHK2/S1P axis that alters the acetylome with a specificity for PASMC, through hyperacetylation of histone H3K9.

Schwarz and the study's first author, Dushani Ranasinghe, Ph.D., who was a member of Schwarz's lab while she was a graduate student at Notre Dame, were also interviewed about their findings for an episode of the "Discover CircRes" podcast, which is produced by Circulation Research.

Schwarz said the next steps for her research include further exploration of the SPHK2 protein as a therapeutic target for pulmonary hypertension, in collaboration with Brian Blagg, director of the Warren Center for Drug Discovery and Development at Notre Dame.

Reference: "Altered Smooth Muscle Cell Histone Acetylome by the SPHK2/S1P Axis Promotes Pulmonary Hypertension" by A. Dushani C.U. Ranasinghe, Maggie Holohan, Kalyn M. Borger, Deborah L. Donahue, Rafael D. Kuc, Martin Gerig, Andrew Kim, Victoria A. Ploplis, Francis J. Castellino and Margaret A. Schwarz, 12 September 2023, Circulation Research.DOI: 10.1161/CIRCRESAHA.123.322740

Other IU authors on the study include Maggie Holohan and Martin Gerig.

This study was made possible in part by funding from the National Institutes of Health, the Lilly Endowment, the O'Brien Family Endowment for Excellence, the National Science Foundation and the Buckner Family Scholarship.

Awareness, Prevention, & Treatment Of Pulmonary Hypertension – What You Need To Know!

MURRAY, Utah (ABC4 Utah) – Pulmonary Hypertension, or PH, is a type of high blood pressure that affects the arteries in the lungs and the right side of the heart. PH is a progressive rare disease is defined by high blood pressure in the lungs and can cause right-heart failure and even death.

PH is a contributing factor to more than 18,000 adult deaths each year in the United States. It can occur among those with left-heart disease; associated conditions such as sleep apnea, chronic obstructive pulmonary disease (COPD) or scleroderma; or from congenital heart disease.

It affects people of any age, sex, race, social or ethnic background, according to Meghan Cirulis, MD, an interventional pulmonologist and critical care physician at Intermountain Health.

The disease is significantly underdiagnosed and misunderstood, even among health care providers. Symptoms, including shortness of breath, fatigue and chest pain, aren't specific to PH and can lead to dangerous delays in diagnosis.

In some people, pulmonary hypertension slowly gets worse and can be life-threatening. There's no cure for pulmonary hypertension. But treatments are available to help you feel better, live longer and improve your quality of life. While PH is incurable, early diagnosis and proper treatment can extend and improve quality of life.

The symptoms of pulmonary hypertension develop slowly. You may not notice them for months or even years. Symptoms get worse as the disease progresses.

Pulmonary hypertension symptoms include:

• Shortness of breath, at first while exercising and eventually while at rest.

• Blue or gray skin color due to low oxygen levels. Depending on your skin color, these changes may be harder or easier to see.

• Chest pressure or pain.

• Dizziness or fainting spells.

• Fast pulse or pounding heartbeat.

• Fatigue.

• Swelling in the ankles, legs and belly area.

One of the challenges with pulmonary hypertension is that symptoms aren't specific to PH and can lead to dangerous delays in diagnosis.

Intermountain Health has an accredited program and highly skilled PH team at the Schmidt Chest Clinic at Intermountain Medical Center in Murray.

The Intermountain Health Pulmonary Hypertension Care Center is a Pulmonary Hypertension Association accredited program that cares for patients with all types of pulmonary vascular disease, including pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH).

The Intermountain PHCC and Cardiovascular Surgery program offer pulmonary thromboendarterectomy surgery for eligible patients with CTEPH.

Visit IntermountainHealth.Org for more information.

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