Target identified for pulmonary hypertension treatment

Graphic depicting a pair of lungs with a stethoscope

Researchers at the Indiana University School of Medicine and the University of Notre Dame have identified a new therapeutic target for the treatment of pulmonary hypertension.

One of the hallmarks of pulmonary hypertension is vascular remodeling, and typically therapies revolve around treating the symptoms of the remodeling rather than the remodeling itself.

But Margaret Schwarz, MD, professor of pediatrics at IU School of Medicine and senior author of the study, said her team has discovered an epigenetic pathway mediated via the protein SPHK2 that can reduce and potentially reverse vascular remodeling in pulmonary hypertension.

“This is one of the very first mechanisms of pulmonary hypertension identified that can be reversible,” Dr. Schwarz said. “Normally, pulmonary hypertension patients are given medications to reduce the vascular pressure on the lungs or to help the heart squeeze better to pump blood, which are both symptoms of cardiovascular 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, she explained, is similar to cancer treatment.

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

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.
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