Chymase bound to heparin is resistant to its natural inhibitors and capable of proteolyzing high density lipoproteins in aortic intimal fluid

Lindstedt, Leena; Lee, Miriam; Kovanen, Petri T.

doi:10.1016/s0021-9150(00)00544-x

Cited by 66 publications

(45 citation statements)

References 42 publications

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“…In fact, chymase treatment of the intimal fluid reduces its ability to promote a high affinity component of efflux from human monocyte-derived macrophage foam cells (25). Moreover, the effects of chymase described here have been observed using a concentration of the enzyme which is within the estimated physiological range in the intima (24). These observations suggest that chymase secretion by activated mast cells present in the arterial intima (50) may reduce the ability of intimal fluid to clear an excess of cellular cholesterol via ABCA1, so contributing to foam cell formation in the atherosclerosis-prone areas of the arterial wall.…”

Section: Figmentioning

confidence: 72%

“…3 to Promote Efflux of Cellular Cholesterol from J774 and Fu5AH Cells-We treated the HDL 3 fractions isolated from human plasma with human chymase for various periods of time. The concentration of chymase used (0.5 g/ml) was chosen to match the assumed concentration of chymase in the intimal fluid (24). After fully inhibiting the chymase activity, the untreated and chymasetreated HDL 3 preparations were added to three cellular systems to test their ability to promote cellular cholesterol efflux.…”

Section: Methodsmentioning

confidence: 99%

“…We selected human chymase as an example of a neutral protease present in the arterial intima because chymase, when bound to heparin, i.e. in its physiological form, is partially resistant to its natural inhibitors (24) and, thus, capable of proteolyzing HDL in the plasma (20) and in the aortic intimal fluid (24,25).…”

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confidence: 99%

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Depletion of Pre-β-high Density Lipoprotein by Human Chymase Impairs ATP-binding Cassette Transporter A1- but Not Scavenger Receptor Class B Type I-mediated Lipid Efflux to High Density Lipoprotein

Favari

Lee

Calabresi

et al. 2004

Journal of Biological Chemistry

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116

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The ATP-binding cassette transporter A1 (ABCA1) mediates the efflux of cellular unesterified cholesterol and phospholipid to lipid-poor apolipoprotein A-I. Chymase, a protease secreted by mast cells, selectively cleaves pre-␤-migrating particles from high density lipoprotein (HDL) 3 and reduces the efflux of cholesterol from macrophages. To evaluate whether this effect is the result of reduction of ABCA1-dependent or -independent pathways of cholesterol efflux, in this study we examined the efflux of cholesterol to preparations of chymase-treated HDL 3 in two types of cell: 1) in J774 murine macrophages endogenously expressing low levels of scavenger receptor class B, type I (SR-BI), and high levels of ABCA1 upon treatment with cAMP; and 2) in Fu5AH rat hepatoma cells endogenously expressing high levels of the SR-BI and low levels of ABCA1. Treatment of HDL 3 with the human chymase resulted in rapid depletion of pre-␤-HDL and a concomitant decrease in the efflux of cholesterol and phospholipid (2-fold and 3-fold, respectively) from the ABCA1-expressing J774 cells. In contrast, efflux of free cholesterol from Fu5AH to chymase-treated and to untreated HDL 3 was similar. Incubation of HDL 3 with phospholipid transfer protein led to an increase in pre-␤-HDL contents as well as in ABCA1-mediated cholesterol efflux. A decreased cholesterol efflux to untreated HDL 3 but not to chymasetreated HDL 3 was observed in ABCA1-expressing J774 with probucol, an inhibitor of cholesterol efflux to lipidpoor apoA-I. Similar results were obtained using brefeldin and gliburide, two inhibitors of ABCA1-mediated efflux. These results indicate that chymase treatment of HDL 3 specifically impairs the ABCA1-dependent pathway without influencing either aqueous or SR-BI-facilitated diffusion and that this effect is caused by depletion of lipid-poor pre-␤-migrating particles in HDL 3 . Our results are compatible with the view that HDL 3 promotes ABCA1-mediated lipid efflux entirely through its lipid-poor fraction with pre-␤ mobility.

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Section: Figmentioning

confidence: 72%

Section: Methodsmentioning

confidence: 99%

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Depletion of Pre-β-high Density Lipoprotein by Human Chymase Impairs ATP-binding Cassette Transporter A1- but Not Scavenger Receptor Class B Type I-mediated Lipid Efflux to High Density Lipoprotein

Favari

Lee

Calabresi

et al. 2004

Journal of Biological Chemistry

Self Cite

116

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“…We have recently determined the mast cell-to-SMC ratio to be 1:5 at the immediate site of erosion and rupture, 11 and we have estimated the concentration of chymase to be 0.6 g/mL in the intimal fluid of such vulnerable areas. 33 This concentration of chymase is equivalent to Ϸ6 BTEE units/ mL. Thus, the cell and chymase concentrations used in this in vitro study reflect the presumptive in vivo situation.…”

Section: Discussionmentioning

confidence: 97%

“…Indeed, it has been shown that heparin proteoglycans can protect chymase from inactivation by its natural inhibitors, such as ␣ 1 -antitrypsin, ␣ 2 -macroglobulin, and ␣ 1 -antichymotrypsin. 33,34 Additionally, it has recently been shown that chymase and interstitial collagenase, known to be present in atherosclerotic lesions, [35][36][37] can avidly hydrolyze and inactivate their natural inhibitors, 38 suggesting that the amount of functional inhibitors are decreased in the atherosclerotic arterial intima. 39 Protease-induced apoptosis is not a specific phenomena for chymase and SMCs, inasmuch as elastase and proteinase 3 (neutrophil serine proteases) can induce the apoptosis of endothelial cells, 40 ␣-chymotrypsin and trypsin can induce the apoptosis of neutrophils, 41 and chymase can induce the apoptosis of cardiomyocytes.…”

Section: Discussionmentioning

confidence: 99%

Mast cell chymase induces apoptosis of vascular smooth muscle cells

et al. 2000

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Abstract-In human coronary atheromas, the numbers of degranulated mast cells and of apoptotic smooth muscle cells (SMCs) are increased. Accordingly, the possibility exists that mast cells participate in the regulation of SMC apoptosis in the lesions. Mast cells isolated from the serosal cavities of rats were stimulated to release their secretory granules. The neutral protease chymase, present in the exocytosed granules, was found to induce apoptosis when added to rat aortic SMCs in culture. The chymase-induced apoptosis of SMCs was detected by flow cytometry, microscopic analysis of cellular morphology, terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL), and electrophoretic demonstration of DNA laddering. Chymase induced SMC apoptosis in a dose-and time-dependent manner, and its proteolytic activity was essential for the proapoptotic effect. In addition to rat chymase, recombinant human chymase was also found to induce apoptosis of human coronary artery SMCs in culture. Key Words: apoptosis Ⅲ smooth muscle Ⅲ atherosclerosis Ⅲ mast cells Ⅲ chymase S mooth muscle cells (SMCs) are the main cellular component in atherosclerotic lesions, and their number and activity largely determine the thickness of the intima. 1 During the final stages of atherosclerosis, the clinical relevance of the thickness of the intima is apparent: a thick intima (fibrous cap) overlying a lipid-rich core of an atheroma protects it from rupturing, whereas a thin cap predisposes it to rupture. 2 The concept has been put forward that the fibrous cap of an atheroma is a dynamic structure in which connective tissue matrix is produced and maintained by SMCs. 3 Accordingly, reduced production of the extracellular matrix due to decreased SMC number, either by necrotic or apoptotic cell death, would weaken the cap and potentiate the risk of cap rupture.Recent findings have demonstrated that SMCs of human coronary and carotid atheromas undergo apoptosis. 4 -7 Interestingly, it has been shown that SMCs isolated from human coronary atherosclerotic plaques are more prone to apoptosis than are SMCs from normal vessels. 8 The SMCs undergoing apoptosis are localized mainly in the fibrous caps of the atheromas and are accompanied by the presence of inflammatory cells. 6,9 In the inflammatory infiltrates, mast cells are also present. 10 -12 Our previous investigations have used isolated rat serosal mast cells, which, like human mast cells, release on stimulation an array of vasoactive mediators, proteoglycans, and neutral proteases. 13,14 The rat mast cells have been shown to be a useful model for studying various molecular aspects relevant to human atherogenesis. 15 Chymase is contained in the cytoplasmic granules of rat serosal mast cells and, on their degranulation, is secreted within expelled granules. 14 In the extracellular fluid, the soluble components of the exocytosed granules (ie, histamine, chondroitin sulfate proteoglycans, and a fraction of heparin sulfate proteoglycans) are solubilized and released from the granules. ...

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Mast Cell Proteases and Atherosclerosis

Kovanen

2010

Atherosclerosis

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Chymase bound to heparin is resistant to its natural inhibitors and capable of proteolyzing high density lipoproteins in aortic intimal fluid

Cited by 66 publications

References 42 publications

Depletion of Pre-β-high Density Lipoprotein by Human Chymase Impairs ATP-binding Cassette Transporter A1- but Not Scavenger Receptor Class B Type I-mediated Lipid Efflux to High Density Lipoprotein

Depletion of Pre-β-high Density Lipoprotein by Human Chymase Impairs ATP-binding Cassette Transporter A1- but Not Scavenger Receptor Class B Type I-mediated Lipid Efflux to High Density Lipoprotein

Mast cell chymase induces apoptosis of vascular smooth muscle cells

Mast Cell Proteases and Atherosclerosis

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