1997

DOI: 10.1002/(sici)1096-9896(199705)182:1<115::aid-path806>3.0.co;2-9

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Mast Cell Distribution, Activation, and Phenotype in Atherosclerotic Lesions of Human Carotid Arteries

Maria Jeziorska

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,

Charles McCollum

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,

³

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Chymase Activity and Localisation In Human Blood Vessels1

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1998

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Cited by 153 publications

(107 citation statements)

References 31 publications

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“…Although previous studies have found increased numbers of mast cells 19,[21][22][23]33 ; MMP-1-, MMP-3-, and MMP-9 -immunopositive cells; and net MMP activity [12][13][14] in the shoulder regions of atherosclerotic plaques, no direct collocation or involvement of mast cells in MMP activation has been reported.…”

Section: Discussionmentioning

confidence: 81%

“…[3][4][5] It has been suggested that mast cells contribute to this process by releasing neutral proteases such as tryptase and chymase. 19,[21][22][23]33 These enzymes, which are released from mast cells by degranulation, may act indirectly by activation of . Caseinolytic in situ zymography in the presence of antipain and chymostatin.…”

Section: Discussionmentioning

confidence: 99%

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Activation of Matrix-Degrading Metalloproteinases by Mast Cell Proteases in Atherosclerotic Plaques

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²

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³

et al. 1998

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Abstract-Recent studies suggest that mast cell-derived neutral proteases can activate matrix-degrading metalloproteinases (MMPs). We have investigated the role of the mast cell proteases tryptase and chymase in the activation of MMPs in human carotid endarterectomy specimens (atherosclerotic, nϭ32) and postmortem carotid arteries (control, nϭ17). In vitro degranulation of mast cells in atherosclerotic carotid arteries by compound 48/80 caused a significant increase in MMP activity. Addition of the nonselective tryptase inhibitor antipain, the specific trypsinlike protease inhibitor 4-amidinophenylmethanesulfonyl fluoride, and the chymase inhibitor chymostatin reduced this increase in MMP activity by 30Ϯ6%, 23Ϯ6%, and 9Ϯ2%, respectively. Immunocytochemistry identified significantly higher numbers of tryptase-containing cells (mast cells) and cells expressing MMP-1 and MMP-3 in the "shoulder" regions of atherosclerotic artery lesions compared with the tunica media of control arteries. Dual immunocytochemistry showed collocation of MMP-1 and MMP-3 with mast cells in the shoulder regions. Degranulation was observed in 78Ϯ5% (meanϮSEM) of mast cells in this area, whereas nonactivated mast cells were observed in all other areas. In situ zymography revealed caseinolytic and gelatinolytic activity in these areas. In conclusion, in vitro mast cell degranulation, which releases mast cell proteases, in carotid arteries increases MMP activity. Furthermore, elevated MMP-1 and MMP-3 expression is collocated with increased numbers of degranulated mast cells and with greater MMP activity in the shoulder regions of atherosclerotic plaques. Activation of MMPs by mast cell-derived proteases may be an important mechanism in atherosclerotic plaque destabilization. (Arterioscler Thromb Vasc Biol. 1998;18:1707-1715.)

“…Although previous studies have found increased numbers of mast cells 19,[21][22][23]33 ; MMP-1-, MMP-3-, and MMP-9 -immunopositive cells; and net MMP activity [12][13][14] in the shoulder regions of atherosclerotic plaques, no direct collocation or involvement of mast cells in MMP activation has been reported.…”

Section: Discussionmentioning

confidence: 81%

“…[3][4][5] It has been suggested that mast cells contribute to this process by releasing neutral proteases such as tryptase and chymase. 19,[21][22][23]33 These enzymes, which are released from mast cells by degranulation, may act indirectly by activation of . Caseinolytic in situ zymography in the presence of antipain and chymostatin.…”

Section: Discussionmentioning

confidence: 99%

Activation of Matrix-Degrading Metalloproteinases by Mast Cell Proteases in Atherosclerotic Plaques

¹

,

²

,

³

et al. 1998

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Abstract-Recent studies suggest that mast cell-derived neutral proteases can activate matrix-degrading metalloproteinases (MMPs). We have investigated the role of the mast cell proteases tryptase and chymase in the activation of MMPs in human carotid endarterectomy specimens (atherosclerotic, nϭ32) and postmortem carotid arteries (control, nϭ17). In vitro degranulation of mast cells in atherosclerotic carotid arteries by compound 48/80 caused a significant increase in MMP activity. Addition of the nonselective tryptase inhibitor antipain, the specific trypsinlike protease inhibitor 4-amidinophenylmethanesulfonyl fluoride, and the chymase inhibitor chymostatin reduced this increase in MMP activity by 30Ϯ6%, 23Ϯ6%, and 9Ϯ2%, respectively. Immunocytochemistry identified significantly higher numbers of tryptase-containing cells (mast cells) and cells expressing MMP-1 and MMP-3 in the "shoulder" regions of atherosclerotic artery lesions compared with the tunica media of control arteries. Dual immunocytochemistry showed collocation of MMP-1 and MMP-3 with mast cells in the shoulder regions. Degranulation was observed in 78Ϯ5% (meanϮSEM) of mast cells in this area, whereas nonactivated mast cells were observed in all other areas. In situ zymography revealed caseinolytic and gelatinolytic activity in these areas. In conclusion, in vitro mast cell degranulation, which releases mast cell proteases, in carotid arteries increases MMP activity. Furthermore, elevated MMP-1 and MMP-3 expression is collocated with increased numbers of degranulated mast cells and with greater MMP activity in the shoulder regions of atherosclerotic plaques. Activation of MMPs by mast cell-derived proteases may be an important mechanism in atherosclerotic plaque destabilization. (Arterioscler Thromb Vasc Biol. 1998;18:1707-1715.)

“…8 Upon maturation, mast cells release and express a wide variety of factors, including the stem cell factor receptor, c-kit 9,10 and the proteases, chymase and tryptase. 11 It has been shown that mast cells can reside in a variety of tissues and organs, including cardiac tissue, 12,13 the gastrointestinal tract 14,15 and the liver. 16,17 Hepatic mast cell number increases with the progression of liver diseases, such as cirrhosis, fibrosis, hepatitis and cholangiopathies.…”

mentioning

confidence: 99%

Inhibition of mast cell-derived histamine secretion by cromolyn sodium treatment decreases biliary hyperplasia in cholestatic rodents

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²

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³

et al. 2014

Laboratory Investigation

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Cholangiopathies are characterized by dysregulation of the balance between biliary growth and loss. We have shown that histamine (HA) stimulates biliary growth via autocrine mechanisms. To evaluate the paracrine effects of mast cell (MC) stabilization on biliary proliferation, sham or BDL rats were treated by IP-implanted osmotic pumps filled with saline or cromolyn sodium (24 mg/kg BW/day (inhibits MC histamine release)) for 1 week. Serum, liver blocks and cholangiocytes were collected. Histidine decarboxylase (HDC) expression was measured using real-time PCR in cholangiocytes. Intrahepatic bile duct mass (IBDM) was evaluated by IHC for CK-19. MC number was determined using toluidine blue staining and correlated to IBDM. Proliferation was evaluated by PCNA expression in liver sections and purified cholangiocytes. We assessed apoptosis using real-time PCR and IHC for BAX. Expression of MC stem factor receptor, c-kit, and the proteases chymase and tryptase were measured by real-time PCR. HA levels were measured in serum by EIA. In vitro, MCs and cholangiocytes were treated with 0.1% BSA (basal) or cromolyn (25 mM) for up to 48 h prior to assessing HDC expression, HA levels and chymase and tryptase expression. Supernatants from MCs treated with or without cromolyn were added to cholangiocytes before measuring (i) proliferation by MTT assays, (ii) HDC gene expression by real-time PCR and (iii) HA release by EIA. In vivo, cromolyn treatment decreased BDL-induced: (i) IBDM, MC number, and biliary proliferation; (ii) HDC and MC marker expression; and (iii) HA levels. Cromolyn treatment increased cholangiocyte apoptosis. In vitro, cromolyn decreased HA release and chymase and tryptase expression in MCs but not in cholangiocytes. Cromolyn-treated MC supernatants decreased biliary proliferation and HA release. These studies provide evidence that MC histamine is key to biliary proliferation and may be a therapeutic target for the treatment of cholangiopathies.

“…Tranilast (a stabilizer of mast cells) completely prevented the increase in chymase-like activity, reduced the chymase mRNA levels by Ϸ40%, and decreased the carotid intima͞media ratio by Ϸ60%. Increased numbers of mast cells and enhanced chymase immunoreactivity and mRNA levels have been documented in atherosclerotic lesions (3,16,17). Inhibition of chymase activity also has been shown to reduce neointima formation in dog vein grafts (18).…”

mentioning

confidence: 99%

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

¹

,

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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