*3.5. Chymase as an Interface for the Activation of Several Pro-fibrogenic Pathways*

The MC chymase activity is increased in the livers of patients with fibrosis or cirrhosis and there is a significant correlation between the chymase level and the degree of fibrosis [147]. Chymase can cleave the Phe8–His9 bond of the non-bioactive peptide angiotensin I (Ang I), forming its bioactive peptide angiotensin II (Ang II) in mammalian tissues including humans [148]. Ang II also induced hepatic fibrosis via the induction of α-SMA in HSCs [149]. Ang II and its angiotensin receptor 1 (AT1) are involved in the fibrotic process. In human fibrosis, MC chymase expression is increased, which is coupled with an increased expression of myofibroblast Ang II receptor, AT1. The receptor is expressed on vascular smooth muscle cells, HSCs, portal myofibroblasts, and hepatocytes. During cirrhosis, the expression of AT1 is increased in fibrotic septa and vessels. Ang II and chymase can bind to AT1 on HSCs and MFBs in fibrotic septa and promote fibrosis [150]. The effect of chymase on isolated HSCs reveals that the protease enhances HSC proliferation, TGF-β1/α-SMA protein expression, and collagen I formation [151]. In addition to the activation of Ang II, chymase was shown to enzymatically cleave the precursors of MMP-9 (pro-gelatinase B), TGF-β, and collagen I, leading to their biologically active forms [152–154]. Furthermore, the enzymatic function of MC-released chymase can produce soluble SCF via enzymatic cleavage of the membrane-bound form of SCF on stromal cells, which induces the formation of mature MCs from immature MCs via the stimulation of KIT [155]. Due to the multiple roles of chymase, which may promote organ fibrosis, this enzyme is a promising target for anti-fibrotic agents [156].
