Cleavage of Type I Procollagen by Human Mast Cell Chymase Initiates Collagen Fibril Formation and Generates a Unique Carboxyl-terminal Propeptide

Kofford, Mark W.; Schwartz, Lawrence B.; Schechter, Norman M.; Yager, Dorne R.; Diegelmann, Robert F.; Graham, Martin F.

doi:10.1074/jbc.272.11.7127

Cited by 181 publications

(118 citation statements)

References 39 publications

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“…However, we cannot exclude MMP-independent effects of mMCP-4 on the connective tissue components. For example, we have shown previously that fibronectin is a substrate for mMCP-4 (36), and it has been shown that MC chymase can degrade type I procollagen (37). Furthermore, chymase has been reported to activate human interstitial procollagenase by cleavage of the Leu 83 -Thr 84 bond (38).…”

Section: Discussionmentioning

confidence: 99%

A Key Role for Mast Cell Chymase in the Activation of Pro-matrix Metalloprotease-9 and Pro-matrix Metalloprotease-2

Tchougounova

Lundequist

Fajardo

et al. 2005

Journal of Biological Chemistry

289

251

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Chymases, serine proteases exclusively expressed by mast cells, have been implicated in various pathological conditions. However, the basis for these activities is not known, i.e. the in vivo substrate(s) for mast cell chymase has not been identified. In this study we show that mice lacking the chymase mouse mast cell protease 4 (mMCP-4) fail to process pro-matrix metalloprotease 9 (pro-MMP-9) to its active form in vivo, whereas both the pro and active form of MMP-9 was found in tissues of wild type mice. Moreover, the processing of pro-MMP-2 into active enzyme was markedly defective in mMCP-4 null animals. Histological analysis revealed an increase in collagen in the ear tissue of mMCP-4-deficient animals accompanied by increased ear thickness and a higher content of hydroxyproline. Furthermore, both lung and ear tissue from the knock-out animals showed a markedly increased staining for fibronectin. MMP-9 and MMP-2 are known to have a range of important activities, but the mechanisms for their activation in vivo have not been clarified previously. The present study thus indicates a key role for mast cell chymase in the regulation of pro-MMP-2 and -9 activities. Moreover, the results suggest an important role for mast cell chymase in regulating connective tissue homeostasis. When mast cells (MCs)1 are activated, they degranulate and thereby release a panel of powerful preformed inflammatory mediators, including histamine, cytokines such as tumor necrosis factor-␣, proteoglycans, and various MC-specific proteases (1, 2). The MC proteases are divided into three main subclasses, tryptases, chymases, and carboxypeptidase A (3-5), all of which are stored in the MC granule in complex with heparin proteoglycan (6, 7). Chymases, serine proteases with chymotrypsin-like substrate specificities, have potent pro-inflammatory properties (8) and have been implicated in a variety of pathophysiological conditions, e.g. angiogenesis (9), heart failure (10), and fibrosis (11). However, it has not been possible to determine the mechanism by which chymases influences these processes, i.e. the physiological substrate(s) for chymase has not been identified.Matrix metalloproteases (MMPs) are known to be involved in a variety of physiological and pathological processes and are currently attracting a large clinical interest as potential drug targets in therapeutic intervention with various diseases (12-16). The MMPs, similar to most proteolytic enzymes, are synthesized with an N-terminal propeptide that needs to be removed to achieve proteolytic activity. Thus, the physiological processes that lead to propeptide cleavage are imperative in terms of regulating the activity of most proteases (17). The MMP family currently comprises Ͼ20 members (18). The members all share common structural features but differ in regard to substrate specificities, although overlapping substrate specificities between certain members of the MMP family occur. Thus, MMP-2 and -9 share the ability to degrade denatured collagen (gelatin) and are therefore also den...

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Section: Discussionmentioning

confidence: 99%

A Key Role for Mast Cell Chymase in the Activation of Pro-matrix Metalloprotease-9 and Pro-matrix Metalloprotease-2

Tchougounova

Lundequist

Fajardo

et al. 2005

Journal of Biological Chemistry

289

251

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“…Heparin facilitates the processing of prochymase [10,11] and β-protryptase [12] by dipeptidylpeptidase I (DPPI, Cathepsin C), a cysteine protease. Chymase converts angiotensin I to angiotensin II [13,14], processes type I procollagen to collagen fibrils [15] and degrades various cytokines [16]. Cathepsin G is serine protease expressed by MC TC cells [17] as well as by neutrophils and monocytes.…”

Section: Introductionmentioning

confidence: 99%

Active monomers of human β-tryptase have expanded substrate specificities

Fukuoka

Schwartz

2007

International Immunopharmacology

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Abstractβ-Tryptase, a product of the TPSAB1 and TPSB2 genes, is a trypsin-like serine protease that is a major and selective component of the secretory granules of all human mast cells, accounting for as much as 25% of cell protein. Once mast cells are activated, β-tryptase is released along with histamine and heparin proteoglycan. β-Tryptase is a unique enzyme with a homotetrameric structure in which active sites face into the central cavity of the four monomers, stabilized by heparin-proteoglycan. This structure makes β-tryptase resistant to most biological inhibitors of serine proteases. Without stabilization, at neutral pH β-tryptase converts to inactive monomers. Tryptase levels are elevated in bronchoalveolar lavage (BAL) fluid obtained from atopic asthmatics and in serum during systemic anaphylactic shock. Several synthetic small molecular weight β-tryptase inhibitors reduced Aginduced airway hypersensitivity in animals, suggesting β-tryptase is involved in the pathogenesis of airway inflammation. Although the major biologic substrate(s) of β-tryptase remain ambiguous, the protease can digest several proteins of potential biologic importance, including fibrinogen, fibronectin, pro-urokinase, pro-matrix metalloprotease-3 (proMMP-3), protease activated receptor-2 (PAR2) and complement component C3. Recently, monomers of β-tryptase with enzymatic activity have been detected in vitro. Here we discuss how β-tryptase monomers with enzymatic activity were identified as well as their potential role in vivo.

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“…Chymases also can influence structural remodeling through their ability to degrade extracellular matrix proteins, including fibronectin and collagen type IV, possibly through activation of matrix metalloproteinases (MMPs) (MMP-1, MMP-3, and MMP-9) (10)(11)(12). Chymases also stimulate collagen fibirillogenesis by cleavage of type I procollagen (13).…”

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confidence: 99%

Conditional and targeted overexpression of vascular chymase causes hypertension in transgenic mice

Gros²,

You³

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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We cloned a rat vascular chymase (RVCH) from smooth muscle cells (SMCs) that converts angiotensin I to II and is up-regulated in SMC from spontaneously hypertensive vs. normotensive rats. To determine whether increased activity of RVCH is sufficient to cause hypertension, transgenic mice were generated with targeted conditional expression of RVCH to SMC, with the use of the tetracyclinecontrolled transactivator (tTA). We confirmed conditional expression of RVCH by mRNA, protein, and chymase activity in the absence, but not in the presence, of dietary doxycycline. The systolic blood pressure (mmHg), measured by carotid artery cannulation at 10 -12 weeks of age, was higher in tTA؉͞RVCH؉ mice than in nonbinary transgenic littermates (136 ؎ 4 vs. 109 ؎ 3) (P < 0.05), as were the diastolic and mean pressures. Hypertension was completely reversed by doxycycline, suggesting a causal link with chymase expression. Medial thickening of mesenteric arteries from tTA؉͞RVCH؉ mice vs. littermates (0.82 ؎ 0.1 vs. 0.42 ؎ 0.02) (P < 0.05) was associated with increased SMC proliferation, as judged by positive immunoreactivity, with the use of an antibody to the proliferating cell nuclear antigen. These structural changes were prevented by doxycycline. Perfusion myography of mesenteric arteries from tTA؉͞RVCH؉ mice also revealed increased vasoconstriction in response to phenylephrine and impaired metacholine-induced vasodilatation when compared with littermate controls or with the doxycyline-treated group. Our studies suggest that up-regulation of this vascular chymase is sufficient to cause a hypertensive arteriopathy, and that RVCH may be a candidate gene and a therapeutic target in patients with high blood pressure.smooth muscle cells C hymases are serine proteinases that were thought to be produced exclusively by mast cells in blood vessels and the myocardium. These enzymes generate angiotensin (Ang) II in large and resistance vessels (1-3) and in the heart (4) and also can convert big-endothelin-1 to endothelin-1 in vitro (5) and inactivate the vasodilator bradykinin (6). That chymase-dependent Ang II formation can occur in the intact animal is evident from studies in the baboon, where it was shown that Ang-converting enzyme inhibitors could not prevent the hemodynamic response to [Pro11, Da1a12]Ang I, which produces Ang II upon incubation with chymase (7). In addition to blood pressure regulation, both Ang II and endothelin-1 are involved in the stimulation of vascular smooth muscle cell (SMC) growth and proliferation, vascular remodeling, and cardiac hypertrophy (8, 9). Chymases also can influence structural remodeling through their ability to degrade extracellular matrix proteins, including fibronectin and collagen type IV, possibly through activation of matrix metalloproteinases (MMPs) (MMP-1, MMP-3, and MMP-9) (10-12). Chymases also stimulate collagen fibirillogenesis by cleavage of type I procollagen (13).Several studies have provided compelling data to suggest that chymases could play a central role in cardiovascular di...

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Cleavage of Type I Procollagen by Human Mast Cell Chymase Initiates Collagen Fibril Formation and Generates a Unique Carboxyl-terminal Propeptide

Cited by 181 publications

References 39 publications

A Key Role for Mast Cell Chymase in the Activation of Pro-matrix Metalloprotease-9 and Pro-matrix Metalloprotease-2

A Key Role for Mast Cell Chymase in the Activation of Pro-matrix Metalloprotease-9 and Pro-matrix Metalloprotease-2

Active monomers of human β-tryptase have expanded substrate specificities

Conditional and targeted overexpression of vascular chymase causes hypertension in transgenic mice

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