PAR1 Protein May Be Target for HAE Treatment
Protease-activated receptor 1 (PAR1), a protein involved in the regulation of blood vessel permeability or leakage, may contribute to hereditary angioedema (HAE) attacks.
That is the preliminary conclusion of a study reporting evidence suggesting that PAR1 was highly activated in the throat tissue of a woman with HAE type 2 who died of an untreated throat swelling attack.
“Based on our observation, both PAR1 and [proteins that activate PAR1] (all of which are current therapeutic targets in other diseases) may be considered as new therapeutic targets in HAE if further studies involving tissue biopsy can confirm our results,” the researchers wrote.
The study, “A novel pathogenetic factor of laryngeal attack in hereditary angioedema? Involvement of protease activated receptor 1,” was published in Allergy, Asthma & Clinical Immunology.
HAE is an inherited condition characterized by sudden and recurrent episodes of swelling in the face, tongue, hands, feet, gastrointestinal tract, genitalia, and upper airways.
These attacks result from excess permeability of small blood vessels caused mainly by overproduction of pro-inflammatory protein, called bradykinin. The fluid that leaks from these vessels builds up in surrounding tissues, causing swelling.
While bradykinin’s role, generation, receptors, and breakdown “are extensively studied and described, the dysfunction of endothelial cells during and preceding the [swelling] process is much less understood,” the researchers wrote.
Endothelial cells — the cells that line blood vessels — have at their surface several protein receptors regulating their permeability and what flows between the bloodstream and surrounding tissues.
One such receptor, called PAR1, was shown previously to increase endothelial cells’ permeability when activated by several molecules that are suppressed by the C1-inhibitor (C1-INH) protein. This protein, known also to block the generation of bradykinin, is abnormally produced in HAE types 1 and 2.
Now, scientists in Hungary found preliminary evidence of PAR1’s potential involvement in swelling attacks and possible hereditary angioedema treatment.
They conducted analyses of throat tissue of a 36-year-old woman with HAE type 2, who died of an untreated swelling attack in the throat.
The woman, whose mother and son also suffered from HAE type 2, had been diagnosed at the age of 22. She had undergone regular follow up, and was experiencing limb swelling “once or twice a year, but airway attacks have never occurred,” the researchers wrote.
One week after the last follow-up visit, she developed progressive facial swelling, followed by swelling of the throat.
According to the researchers, she dismissed her swelling symptoms as non-serious and decided not to use the emergency treatment available in her home — plasma-derived C1-IHN concentrate, which includes CSL Behring’s Berinert and Takeda Pharmaceuticals’ Cinryze. She died at home from suffocation.
When compared with the throat tissue of a 37-year-old woman with no signs of angioedema who had died from kidney disease, the HAE patient showed a marked increase in certain immune cells (specifically T-cells and myeloid cells).
C1-INH levels were slightly higher in the woman with HAE, which was not surprising given that type 2 HAE is characterized by normal C1-INH production, but reduced function.
Bradykinin receptors activated
In addition, the HAE patient’s tissue also showed a slight reduction in both bradykinin receptors at the surface of cells. Since the activation of these cell surface receptors promotes their internalization, “this suggests that both bradykinin receptors were activated during the HAE attack of our patient,” the researchers wrote.
Notably, the woman with HAE showed pronounced lower levels of PAR1 on the surface of not only endothelial cells, but also other cells. Similar to bradykinin receptors, PAR1 is transported from the cell surface to its interior upon activation, suggesting that PAR1 signaling was overactive at the site of the swelling attack.
“Our most important and novel observation was that the PAR1 [level] was strongly reduced in the [HAE] patient compared to the control patient,” the team wrote.
This case highlights that “studying the molecular and cellular mechanisms” of HAE attacks in human tissues “is a necessary future target besides blood plasma analysis,” the researchers wrote.
“On the one hand, our unique case and novel results confirmed those observed in [blood] (e.g., regarding data on C1-INH), on the other hand, it suggested new information about the [mechanism behind] HAE attack[s], which seems to be much more complex than we had thought before,” the team concluded.
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