Multiple Mechanisms for the Action of Chymase Inhibitors

Abstract

Abstract. Angiotensin II plays an important role in regulating blood pressure. Moreover, angiotensin II directly promotes organ damage by inducing expression of various genes, such as transforming growth factor (TGF)-β and matrix metalloproteinase (MMP)-9 precursors. Blockade of angiotensin II has been shown to not only lower blood pressure, but also to prevent cardiovascular and renal dysfunction and fibrosis. Inhibition of TGF-β and MMP-9 has also been shown to prevent cardiovascular and renal damage. A mast cell-produced enzyme, chymase, generates angiotensin II and also converts precursors of TGF-β and MMP-9 to their active forms. Chymase also strongly promotes accumulation of inflammatory cells. These multiple functions of chymase may play an important role in the development and promotion of various diseases. In fact, chymase inhibitors have been shown to prevent nonalcoholic steatohepatitis, intestinal inflammation, and adhesion formation after surgery and cardiovascular and renal damage. On the other hand, chymase inhibitors, unlike angiotensin-converting enzyme inhibitors and angiotensin II blockers, have no blood pressure-lowering effect despite blocking angiotensin II formation. Thus, chymase inhibitors may be useful for preventing damage to various organs via multiple mechanisms without lowering blood pressure.

Chymase Inhibition Attenuates Lipopolysaccharide/ <smlcap>D</smlcap>-Galactosamine-Induced Acute Liver Failure in Hamsters

“…Chymase is co-stored with heparin proteoglycan in the secretory granules of mast cells. Chymase is dispersed from the mast cells immediately after mast cell degranulation, and the activity of dispersed chymase into interstitial tissues is maintained several days after degranulation [28]. Therefore, in the present study, up-regulated chymase activity might have been observed from 1 h until 24 h after LPS/GalN injection.…”

“…The other specific chymase inhibitor, NK3201, has also shown MMP-9 inhibitory effects in various disease models [25,26,27]. Although chymase inhibitors cannot directly inhibit MMP-9 activity, chymase inhibition may be useful for the reduction of MMP-9 activity via prevention of the conversion of MMP-9 from pro-MMP-9 [28]. Thus, the attenuation of hepatic MMP-9 activity by TY-51469 might contribute to reducing the symptoms of ALF after LPS/GalN injection.…”

Are mast cells important in diabetes?

“…Moreover, diabetes mellitus may present inhibition of mast cell activation, a decrease of leukocyte-endothelial cell interactions, reduced numbers of leukocytes in inflammatory sites, a decrease of microvascular responses to inflammatory compounds, including histamine, a reduction in protein loss, and a decrease of acute inflammatory reactions [80].…”

“…Therefore, inhibition of activated MCs and their degranulation and/or inflammatory cytokine/chemokine generation might act to protect pancreatic β cells in T1DM [11].…”

Clonal Expansion of T Cells in Abdominal Aortic Aneurysm: A Role for Doxycycline as Drug of Choice?

“…Therefore, we postulate that the primary effect of doxycycline is based on its inhibition of mitochondrial protein synthesis, preventing clonal expansion of T-cells and possibly also other proliferating cells in AAA tissue, thus, indirectly, resulting in a decrease of proinflammatory cytokines, MMP-2 and MMP-9 that otherwise damage the vascular stroma [9,28,41]. Whilst there is no direct experimental evidence available that the observed effects of doxycycline on AAA are based on its inhibition of mitochondrial protein synthesis, the finding of Lu et al [11] that aneurysmal lesions contain clonally expanded T cells combined with our own observations in cancer research that doxycycline results in a proliferation arrests of T cells through its inhibition of mitochondrial protein synthesis [72,73] lends strong support to our hypothesis.…”