SPHK2 protein may offer way to reverse pulmonary hypertension

Study suggests targeting protein or epigenetic changes that it causes

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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A protein called SPHK2 helps to drive pulmonary hypertension (PH) by changing the epigenetic profiles of cells in blood vessels, a study reports.

Epigenetics refers to changes in gene activity that do not change the genetic code itself.

As such, study findings imply that blocking SPHK2 or otherwise reversing the epigenetic modifications it causes may be viable approaches for the treatment of PH.

“This is one of the very first mechanisms of pulmonary hypertension identified that can be reversible,” Margaret Schwarz, MD, the study’s senior author and a professor of pediatrics at Indiana University’s School of Medicine, said in a university press release.

“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,” Schwarz said.

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The study, “Altered Smooth Muscle Cell Histone Acetylome by the SPHK2/S1P Axis Promotes Pulmonary Hypertension,” was published in Circulation Research

Epigenetics refers to the study of how DNA is packaged within cells or genes are silenced and cannot be converted into proteins. This has profound effects on cellular activities.

The SPHK2 protein is responsible for making a specific type of epigenetic modification called acetyl-H3K9 or Ac-H3K9, which normally is responsible for “unpacking” certain genes when cells are actively growing or when there’s inflammation.

Researchers first examined levels of the Ac-H3K9 modification in 40 lung samples, 20 from people with idiopathic pulmonary arterial hypertension (iPAH), and 20 from people without PH. Results suggested that the Ac-H3K9 modification was present at significantly higher levels in cells from PH lungs.

They also found that Ac-H3K9 was increased in the lungs of a mouse model of PH induced by low oxygen levels. Further, mice in this model that were engineered to lack the SPHK2 protein had less of the Ac-H3K9 modification and were resistant to developing PH.

PH is marked by the excessive growth of cells around the lungs’ blood vessels, which contributes to increased blood pressure as vessel walls become thicker, narrowing the space for blood to flow. In additional cellular experiments, the researchers showed that SPHK2 promotes the growth of muscle cells around lung blood vessels, implying a role for this molecular pathway in disease development.

Results specifically suggested that this SPHK2-mediated pathway triggers epigenetic changes in a gene called KLF4, which is known to be a key driver of cell growth. Activation of SPHK2 in the muscle cells around blood vessels, in turn, was triggered by a proinflammatory signaling molecule called EMAPII.

This study “cogently explains when, what, and how a disruption of epigenetic equilibrium can occur in PH,” the researchers concluded.

Its findings imply that treatments blocking SPHK2, or otherwise reversing these epigenetic changes, might act to reverse some of the cellular mechanisms that drive PH. According to Schwarz, such a treatment might be able “to stop the vascular remodeling process entirely.”

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