Newborn PH May Be Triggered by Lack of AMPK Protein: Mouse Study
Findings may help scientists develop new therapies to prevent premature deaths
Mice that lack a protein called AMPK in the muscle around their blood vessels develop a lethal disease that appears very similar to persistent pulmonary hypertension of the newborn (PPHN), suggesting that AMPK may be a useful therapeutic target in this disease, according to a new study.
“This study opens a window to unforeseen therapeutic horizons that are so desperately needed to enable better management of this fatal disease,” Mark Evans, PhD, a professor at the University of Edinburgh and senior author of the study, said in a press release.
The study, “AMPK deficiency in smooth muscles causes persistent pulmonary hypertension of the new-born and premature death,” was published in the journal Nature Communications.
What is AMPK?
The AMPK protein is known to be important for regulating energy usage in cells. Recent evidence has suggested that this protein may help to regulate the activity of lung blood vessels, but its role in disease remains incompletely understood.
To learn more about this protein’s function, researchers used genetic engineering to create mice that lacked AMPK only in their smooth muscle, the muscle tissue that wraps around blood vessels and helps push blood through circulation.
To the researchers’ surprise, all of these mice died several weeks after birth, with none surviving beyond 12 weeks — roughly the equivalent of five years old in a human.
Seeking to understand the reason for these unexpected deaths, the scientists conducted detailed analyses of the mice’s bodies. Among the noteworthy results, the team found that lung blood vessels and the right side of the heart were abnormally thick, and there were changes in the structure of alveoli (tiny sack-like structures that hold air in the lungs).
Only lung blood vessels showed structural abnormalities in these mice — blood vessels throughout the rest of the body appeared normal. As such, the researchers concluded that premature death in these mice was most likely a result of complications related to pulmonary hypertension.
Collectively, the changes in the mice’s tissue “are most consistent with persistent pulmonary hypertension of the new-born,” as compared with than any disease or other form of pulmonary hypertension, the researchers wrote. PPHN is a potentially fatal disorder characterized by increased pressure in an infant’s blood vessels.
A further battery of tests on young AMPK-knockout mice showed that lacking this enzyme in smooth muscle led to the development of measurable pulmonary hypertension after birth, with consistent changes in tissue structure — again, the changes were broadly consistent with PPHN.
Additional tests using smooth muscle cells in dishes showed that the loss of AMPK led to dysfunction of mitochondria — cellular structures that play a central role in energy generation — and an increase in levels of toxic molecules called reactive oxygen species (ROS). Loss of AMPK also reduced the activity of a protein called KV1.5, whose reduced activity is a hallmark of persistent pulmonary hypertension in newborns.
“The present study provides the first direct evidence that the induction of PPHN after birth may be triggered by [AMPK] insufficiency in pulmonary arterial myocytes [muscle cells],” the researchers concluded, adding that these findings “might afford new … therapeutic strategies against PPHN.”
The team stressed that more research is needed to determine exactly how the loss of AMPK leads to the development of PPHN-like disease.