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Page 6 of 14 Borek et al. Rare Dis Orphan Drugs J 2023;2:5 https://dx.doi.org/10.20517/rdodj.2022.20

PAH patients show increased serum levels of angiotensin II as well as elevation of the RAAS activity in the
[85]
pulmonary vasculature, contributing to vasoconstriction, vascular remodeling, and disease development .
Thromboembolic lesions are another significant pathology commonly found in the pulmonary vasculature
[86]
of PAH patients . CatG-mediated activation of protease-activated receptor 4 (PAR4) on platelets
stimulates their aggregation, granule secretion, and leukocyte interaction [87,88] , thereby contributing to the
thrombo-inflammatory process in the vessels. Furthermore, CatG is involved in chemotaxis regulation. It
generates active forms of CXCL5 and CCL15, thus providing a signal for the accumulation of neutrophils
and monocytes, respectively [89,90] . Additionally, similar to other cathepsins, CatG is also involved in
proteolytic antigen processing by antigen-presenting cells .
[91]

MAST CELL SERINE PROTEASES IN PAH
Neutrophil NSPs are not the only serine proteases implicated in PAH. There is also a body of evidence that
links mast cell (MCs) proteolytic activity to the pathogenic process in this disease. Indeed, accumulation of
MCs is commonly observed in and around the remodeled vessel [31,92] and their depletion , as well as
[28]
inhibition of MC degranulation, ameliorates experimental PH [28,93] . Mast cells are a tissue-resident, long-
lived granulocyte population that resides at the host-external environment interface, often in proximity to
blood vessels. They play an important homeostatic role, coordinating inflammatory and repair processes in
the tissue. Despite being very rare, the biological response evoked by MCs products can be extremely
potent. Inappropriate MC activity contributes to acute allergic responses, chronic inflammation, and tissue
remodeling and has been linked not only to pathology in PAH but also to other chronic pulmonary
diseases, e.g., asthma, pulmonary fibrosis, and COPD . Proteases can make up over 25% of total protein
[94]
content in MCs, with mRNA levels that exceed commonly used housekeeping genes [95-97] . Two of the most
[98]
abundant MC serine proteases, tryptase and chymase , have been reported to be increased in PAH [92,93] .
Higher levels of circulating MC proteases, and expansion of tryptase and chymase-positive cells in the lung,
correlate with the severity of the pulmonary vascular disease [31,92,99] .

Tryptase
Tryptase can activate protease-activated receptor 2 (PAR2), which increased expression has been found in
PASMCs in vascular lesions. The tryptase-PAR2 axis has been shown to regulate several cellular effects
central to PAH pathogenesis. Primary PASMCs exposed to tryptase increase their proliferation, migration,
and production of fibronectin and MMP-2 .
[31]
Tryptase can also alter the behavior of endothelial cells and stimulate them to release neutrophil-
chemotactic IL-8 [100,101] , and degrade collagen IV, which is a major constituent of the pulmonary vessels’
basement membrane, important for endothelial barrier function [54,102] . Furthermore, deposition of collagen is
commonly observed within remodeled vessels [6,35] . Tryptase activity could facilitate this process via its ability
to stimulate fibroblast proliferation, migration, and collagen I production [103-105] . In conclusion, tryptase
exerts variable effects on different cell types, which cumulatively can contribute to vessel remodeling.

Chymase
Chymase, similar to CatG, has chymotrypsin-like activity. Chymase can directly (independently of
angiotensin-converting enzymes) mediate local production of angiotensin II and activate endothelin, thus
affecting vasomotor tone regulation [106,107] . Indeed, transgenic mice that express human chymase develop
systemic hypertension, cardiac hypertrophy, and leucocytosis, confirming the important role of this enzyme
in the regulation of blood pressure and inflammation . The potentially destructive nature of the increased
[108]
level of chymase is further proven by the observation that a high gene copy number in homozygotes is