Blocking Specific PI3K Protein Prevents PH in Animal Models
Targeting a protein called p110a, a part of the PI3K family of enzymes, may be useful for preventing or even reversing pulmonary hypertension, research done in cells and rodent models showed.
“Targeted inhibition of [p110a] offers a disease-modifying treatment approach, which is readily accessible by small molecule inhibitors and warrants further evaluation in clinical trials,” the researchers wrote.
Results of the study “Disrupted PI3K subunit p110α signaling protects against pulmonary hypertension and reverses established disease in rodents,” were published in The Journal of Clinical Investigation.
Pulmonary hypertension (PH) is characterized by changes in the biological activity of pulmonary arterial smooth muscle cells (PASMCs), the cells that line the lung’s blood vessels. In PH, PASMCs tend to grow more than is normal and become resistant to apoptosis, a form of programmed cell death.
These phenomena are thought to be largely driven by the activation of certain protein receptors — specifically, receptors for growth factors — on the surface of pulmonary arterial smooth muscle cells. Growth factors, as its name suggests, are signaling molecules that can prompt cells to grow.
When a growth factor binds to its receptor, it sends biochemical signals into the cell that affect its activity, like prompting cell division and growth.
A team led by researchers at the University of Cologne in Germany showed that, for many of the growth factor receptors involved in the abnormal PASMC activity that marks PH, these signals are mediated by PI3K enzymes, a well-studied group of proteins that are known to be important for sending several kinds of signals within cells.
Researchers demonstrated that blocking the activity of growth factor receptors lowered PI3K activity. They also reported evidence of increased PI3K activity in mouse models of PH, and in lung tissue from PH patients.
“Our data demonstrated that PI3K is crucial for growth factor–induced responses in [PASMCs], and PI3K activity was profoundly enhanced in remodeled vessels in human and experimental PH,” the researchers wrote.
Since PI3K enzymes are important to many areas of health, broadly inhibiting PI3K activity is not feasible as a treatment strategy. So experiments were done to identify the particular enzyme mainly involved in PH, which might be more useful as a target for therapies.
This work identified a PI3K protein called p110 alpha (p110a). The researchers showed that pulmonary arterial smooth muscle cells engineered to lack p100a could not respond to growth factors in the manner characteristic of PH, and mice without p100a in their PASMCs were resistant to disease development.
Further tests showed that blocking p110a activity pharmacologically lessened signs of PH — such as increased pressure in the lung’s blood vessels, and more strain on the right side of the heart — in mouse and rat models of the disease.
“Both genetic ablation and pharmacological inhibition of [p110a] nearly completely abrogated remodeling of the small pulmonary arteries and largely prevented the development of PH,” the researchers wrote.
“Targeting p110α prevented and even reversed all central features of PH, including vascular remodeling, which is not mitigated by current therapies,” they added.
While less toxic than global PI3K inhibition, blocking p110a has been linked in prior studies with safety concern like abnormal blood sugar levels, the researchers noted. They suggested that directly administering a potential therapy to the lungs might help to lessen such safety problems.
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