Matrix Metalloproteinases-3, -7, and -12, but Not -9, Reduce High Density Lipoprotein-induced Cholesterol Efflux from Human Macrophage Foam Cells by Truncation of the Carboxyl Terminus of Apolipoprotein A-I

Lindstedt, Leena; Saarinen, Jyrki; Kalkkinen, Nisse; Welgus, Howard G.; Kovanen, Petri T.

doi:10.1074/jbc.274.32.22627

Cited by 60 publications

(57 citation statements)

References 60 publications

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“…Stromelysin degrades almost all of the apoA-I without causing any apparent change in apoA-II, whereas the 92 kDa gelatinase appears to degrade apoA-II only (28). The present results with rHDL containing either apoA-I or apoA-II as a single protein component show that chymase clearly distinguishes between apoA-I, which is degraded, and apoA-II, which is completely resistant to proteolytic digestion by the enzyme.…”

Section: Discussionsupporting

confidence: 50%

Apolipoprotein composition and particle size affect HDL degradation by chymase: effect on cellular cholesterol efflux

Lee

Kovanen

Tedeschi

et al. 2003

Journal of Lipid Research

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Mast cell chymase, a chymotrypsin-like neutral protease, can proteolyze HDL 3 . Here we studied the ability of rat and human chymase to proteolyze discoidal pre ␤ -migrating reconstituted HDL particles (rHDLs) containing either apolipoprotein A-I (apoA-I) or apoA-II. Both chymases cleaved apoA-I in rHDL at identical sites, either at the N-terminus (Tyr 18 or Phe 33 ) or at the C-terminus (Phe 225 ), so generating three major truncated polypeptides that remained bound to the rHDL. The cleavage sites were independent of the size of the rHDL particles, but small particles were more susceptible to degradation than bigger ones. Chymase-induced truncation of apoA-I yielded functionally compromised rHDL with reduced ability to promote cellular cholesterol efflux. In sharp contrast to apoA-I, apoA-II was resistant to degradation. However, when apoA-II was present in rHDL that also contained apoA-I, it was degraded by chymase. We conclude that chymase reduces the ability of apoA-I in discoidal rHDL particles to induce cholesterol efflux by cleaving off either its amino-or carboxy-terminal portion. This observation supports the concept that limited extracellular proteolysis of apoA-I is one pathophysiologic mechanism leading to the generation and maintenance of foam cells in atherosclerotic lesions. Chymases are neutral proteases whose specificity is chymotrypsin-like: peptide bonds are cleaved on the carbonyl side of a ) aromatic residues with the order of preference Phe Ͼ Tyr ϾϾ Trp, and b ) the branched aliphatic amino acids Val, Ileu, and Leu (1). These enzymes are produced mainly or exclusively by mast cells, and are also found in mast cells of the human arterial intima, the site of atherogenesis (2). In atherosclerotic lesions, the mast cells are activated and release a fraction of their chymase-containing cytoplasmic secretory granules into their microenvironment, where chymase may act on extracellularly located substrates.Chymase of rat serosal mast cells (rat mast cell protease

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Section: Discussionsupporting

confidence: 50%

Apolipoprotein composition and particle size affect HDL degradation by chymase: effect on cellular cholesterol efflux

Lee

Kovanen

Tedeschi

et al. 2003

Journal of Lipid Research

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“…Previous in vitro studies demonstrated that several proteases, including matrix metalloproteases (14), plasmin and kallikrein (15), and two mast cell proteases, chymase and tryptase (8), can degrade apoA-I present in preb-HDL particles, thereby impairing cellular cholesterol efflux. In this report, we show that TTR has a similar effect: not only does TTR cleave apoA-I in the C terminus after the same residue as chymase (phenylalanine 225) (5), but TTR also is more effective at cleaving apoA-I present in lipid-poor preb-HDL particles, resulting in an impairment in the ability of rHDL to promote cholesterol efflux from macrophages.…”

Section: Discussionmentioning

confidence: 99%

“…In fact, several proteases found in the arterial intima, such as elastase (13), metalloproteases (14), plasmin and plasma kallikrein (15), and the mast cell proteases chymase and tryptase (8), degrade apoA-I in preb-HDL particles in vitro. A crucial prerequisite for the action of HDL particles as efficient acceptors of cellular cholesterol is their integrity; in agreement with this concept, apoA-I cleavage by the above proteases has been widely demonstrated to impair the high-affinity component of cellular cholesterol efflux.…”

Section: Supplementary Abstract High Density Lipoprotein and Reverse Cmentioning

confidence: 99%

ApoA-I cleaved by transthyretin has reduced ability to promote cholesterol efflux and increased amyloidogenicity

Liz

Gomes

Saraiva

et al. 2007

Journal of Lipid Research

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A fraction of plasma transthyretin (TTR) circulates in HDL through binding to apolipoprotein A-I (apoA-I). Moreover, TTR is able to cleave the C terminus of lipid-free apoA-I. In this study, we addressed the relevance of apoA-I cleavage by TTR in lipoprotein metabolism and in the formation of apoA-I amyloid fibrils. We determined that TTR may also cleave lipidated apoA-I, with cleavage being more effective in the lipid-poor preb-HDL subpopulation. Upon TTR cleavage, discoidal HDL particles displayed a reduced capacity to promote cholesterol efflux from cholesterol-loaded THP-1 macrophages. In similar assays, TTR-containing HDL from mice expressing human TTR in a TTR knockout background had a decreased ability to perform reverse cholesterol transport compared with similar particles from TTR knockout mice, reinforcing the notion that cleavage by TTR reduces the ability of apoA-I to promote cholesterol efflux. As amyloid deposits composed of N-terminal apoA-I fragments are common in the atherosclerotic intima, we assessed the impact of TTR cleavage on apoA-I aggregation and fibrillar growth. We determined that TTR-cleaved apoA-I has a high propensity to form aggregated particles and that it formed fibrils faster than full-length apoA-I, as assessed by electron microscopy. Our results show that apoA-I cleavage by TTR may affect HDL biology and the development of atherosclerosis by reducing cholesterol efflux and increasing the apoA-I amyloidogenic potential.-Liz, M. A., C. M. Gomes, M. J. Saraiva, and M. M. Sousa. ApoA-I cleaved by transthyretin has reduced ability to promote cholesterol efflux and increased amyloidogenicity. J. Lipid Res. 2007Res. . 48: 2385Res. -2395

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“…The mast cell proteases chymase (20) and tryptase (21) and some metalloproteinases (22) as well as plasmin and kallikrein (23) specifically deplete the small subpopulation of pre-␤-migrating HDL particles and so impair the efflux of cholesterol from human macrophage foam cells promoted by HDL 3 . Because cholesterol efflux to HDL 3 can be mediated by ABCA1-dependent and -independent mechanisms, we were interested to find out which of these two types of efflux is affected by proteolytic enzymes capable of depleting pre-␤-migrating HDL particles.…”

mentioning

confidence: 99%

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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Matrix Metalloproteinases-3, -7, and -12, but Not -9, Reduce High Density Lipoprotein-induced Cholesterol Efflux from Human Macrophage Foam Cells by Truncation of the Carboxyl Terminus of Apolipoprotein A-I

Cited by 60 publications

References 60 publications

Apolipoprotein composition and particle size affect HDL degradation by chymase: effect on cellular cholesterol efflux

Apolipoprotein composition and particle size affect HDL degradation by chymase: effect on cellular cholesterol efflux

ApoA-I cleaved by transthyretin has reduced ability to promote cholesterol efflux and increased amyloidogenicity

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

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