Signaling molecule shows promise in reducing PAH severity
Mouse study points to CNP molecule as potential therapeutic target
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A study found that a naturally occurring signaling molecule called C-type natriuretic peptide (CNP) reduced the severity of pulmonary arterial hypertension (PAH) in mice.
“This study highlights the important role of [CNP] signaling in the [disease development] of PAH and suggests that modulation of this pathway may provide a potential therapeutic approach for PAH in humans,” researchers wrote in the study, “Endothelial C-type natriuretic peptide/guanylyl cyclase-B signaling prevents pulmonary arterial hypertension,” published in Nature Communications.
PAH is marked by high pressure in the pulmonary arteries, the vessels that carry blood from the heart through the lungs. High pressure in these vessels puts abnormal strain on the heart and can cause pulmonary hypertension symptoms such as fatigue and shortness of breath.
CNP is a hormone that’s naturally produced by endothelial cells (the cells that line the inside of blood vessels), and previous studies have shown it’s important for regulating blood pressure and blood vessel health. But while this hormone is known to affect blood vessel biology, its role in PAH remains unclear.
“CNP has been studied mainly in cardiovascular biology, but we wondered whether it might also play an important protective role in pulmonary vascular disease,” Hiromu Yanagisawa, the study’s first author and a researcher at Kyoto University in Japan, said in a university news story. Previous studies in rat models of pulmonary hypertension had conflicting results, the team noted.
Mouse experiments
Yanagisawa and colleagues conducted a series of experiments using two mouse models of PAH, one using a chemical called monocrotaline pyrrole and one exposing the mice to chronic low oxygen levels. In parallel, the researchers also analyzed human cell models and lung tissue from people with PAH.
The researchers found evidence that CNP levels are generally decreased in PAH. Levels of the main molecular receptor for CNP, guanylyl cyclase-B (GC-B), were also reduced, suggesting an overall decrease in activity of the CNP signaling pathway.
To further evaluate the role of this hormone, the researchers then engineered mice that would not produce CNP or the GC-B receptor in endothelial cells. These mice developed more severe disease and higher activity of genes coding for inflammatory molecules. However, mice lacking the GC-B receptor in vascular smooth muscle (the muscle cells that surround blood vessels) did not exhibit these effects, suggesting that the role of this receptor in endothelial cells is crucial.
“These results indicate that a decrease in endothelial CNP/GC-B signaling plays an important role in the progression of PAH,” the researchers wrote.
They also found that administering CNP to mice could prevent the development of PAH both in unaltered mice and in mice lacking GC-B in vascular muscle. But in mice lacking this receptor in their endothelial cells, CNP treatment didn’t affect PAH development. In addition, CNP suppressed the overactivity of proinflammatory genes triggered by low oxygen levels.
In an additional experiment, the scientists used a mouse model of PAH to assess the potential benefits of a form of CNP in combination with current PAH treatments. While each therapy alone reduced the pressure inside the heart’s right ventricle (which pumps blood to the lungs) and eased the disease-associated enlargement of the right ventricle, greater benefits were found when CNP was used in combination with macitentan (sold on its own as Opsumit or in combination with tadalafil as Opsynvi) or Winrevair (sotatercept).
Collectively, the data indicate that CNP signaling through the GC-B receptor on endothelial cells that line blood vessels can reduce the severity or prevent the development of PAH. The data suggest the CNP/GC-B pathway as a potential treatment target in PAH, the researchers said, calling for further studies to explore this possibility.
“This study builds on many years of research in our laboratory, so it was especially meaningful for us to uncover a new protective role for endothelial CNP/GC-B signaling in PAH,” Yanagisawa said. “We hope this will pave the way toward new treatment strategies for patients with PAH.”
