Oxidized low density lipoprotein inhibits platelet plasma membrane Ca2+-ATPase

Zhao, Bin; Dierichs, R.; Miller, Frederick N.; Dean, William L.

doi:10.1016/s0143-4160(96)90118-9

Cited by 37 publications

(25 citation statements)

References 29 publications

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“…43 Finally, even trace amounts of lipid peroxides, isoprostanes, and platelet-activating factor-like substances may be important. However, some potentially formed oxidized lipids reportedly inhibit platelet function (eg, oxysterols, 44 lysolecithin, and 4-hydroxynonenal 45 ); no change in platelet plasma membrane fluidity is induced by Cu 2ϩ -oxLDL, 46 and hypochlorite-treated phosphatidylcholine vesicles could never induce platelet aggregation (authors' unpublished data, 2000). Furthermore, platelet shape change is observed immediately after the addition of hypoxLDL, indicating that the transfer of oxidized lipids or lipophilic low molecular weight components of LDL is not essential for hypoxLDL-induced platelet aggregation.…”

Section: Discussionmentioning

confidence: 99%

Modification of Protein Moiety of Human Low Density Lipoprotein by Hypochlorite Generates Strong Platelet Agonist

Volf

Bielek

Moeslinger

et al. 2000

ATVB

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Abstract-Conflicting reports exist about the effects of mildly or extensively oxidized low density lipoproteins (LDLs) on the reactivity of human platelets. This platelet response is mainly caused by modification of the protein and lipid moiety, giving rise to very differently modified species with hardly predictable properties. The aim of this study was to prepare oxidized LDL with modifications essentially restricted to the protein moiety and to determine the eventual platelet responses. We treated LDL at 0°C for 10 minutes with a 60-to 1000-fold molar excess of sodium hypochlorite in borate buffer in the presence of the radical scavenger butylated hydroxytoluene. Under these conditions, neither fragmentation of apolipoprotein B-100 nor formation of LDL aggregates was observed, and lipid oxidation products did not exceed the amount present in untreated LDLs. The degree of modification and the respective effects on platelet function were highly reproducible. Hypochlorite-modified LDLs act as strong platelet agonists, inducing morphological changes, dense granule release, and irreversible platelet aggregation. The evoked platelet effects are completely suppressed by inhibitors of the phosphoinositide cycle but not by EDTA or acetylsalicylic acid. Most likely, these effects are transmitted via high-affinity binding to a single class of sites, which does not recognize native or acetylated LDL. Obviously, modified lysines, and the secondary lipid modifications derived from them, are not essential for this interaction. We conclude that bioactive oxidized lipids are not directly involved in the stimulation of platelets by hypochlorite-modified LDLs. Key Words: atherosclerosis Ⅲ oxidized LDL Ⅲ apoB-100 Ⅲ human platelets Ⅲ platelet aggregation P latelet-vessel wall interaction (adhesion) and plateletplatelet interaction (aggregation) play a central role in vascular occlusion but are also involved in the earlier stages of development of atherosclerotic plaques. 1 Therefore, conditions leading to altered platelet function are accompanied with an enhanced risk of atherosclerosis and thrombosis. 2 Among others, severe disorders of plasma lipids lead to enhanced platelet reactivity. In particular, it has been known for Ͼ25 years that platelets from hyperlipidemic patients are hyperreactive. 3 Furthermore, LDLs from patients with homozygous familial hypercholesterolemia show enhanced susceptibility to oxidative modification, 4 thus generating a form that is substantially more atherogenic than unmodified LDLs. 5 Native LDLs (nLDLs) reportedly stimulate human platelets, 6,7 but minimally modified LDLs rather than nLDLs may be responsible for these effects. 8,9 LDLs oxidized in vitro by various agents (oxLDLs) showed even more pronounced platelet activation. 10 Because activated platelets may themselves contribute to oxidative modification of LDLs, 11 the platelet-stimulatory effect of plasma lipoproteins is potentially a key event in atherogenesis.Free radicals as well as nonradical oxidants are involved in the oxidative modif...

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Section: Discussionmentioning

confidence: 99%

Modification of Protein Moiety of Human Low Density Lipoprotein by Hypochlorite Generates Strong Platelet Agonist

Volf

Bielek

Moeslinger

et al. 2000

ATVB

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“…We therefore suggest that an impairment of the calcium pumps accounts for the increased basal [Ca 2ϩ ] i level and non-physiological gradient. One mechanism that is likely to be involved in this process is the generation of oxygen radical species, which are not only released in abundance by acinar cells during pancreatitis but are also known to inhibit calcium pumps (40,41,42).…”

Section: Fig 9 Effect Of the Intracellular Camentioning

confidence: 99%

Early Changes in Pancreatic Acinar Cell Calcium Signaling after Pancreatic Duct Obstruction

Mooren¹,

Hlouschek²,

Finkes³

et al. 2003

Journal of Biological Chemistry

115

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Intracellular Ca2؉ -changes not only participate in important signaling pathways but have also been implicated in a number of disease states including acute pancreatitis. To investigate the underlying mechanisms in an experimental model mimicking human gallstone-induced pancreatitis, we ligated the pancreatic duct of Sprague-Dawley rats and NMRI mice for up to 6 h and studied intrapancreatic changes including the dynamics of [ influx in response to secretagogue stimulation. Serum pancreatic enzyme elevation as well as trypsinogen activation was significantly reduced by pretreatment of animals with the calcium chelator BAPTA-AM. These experiments suggest that pancreatic duct obstruction rapidly changes the physiological response of the exocrine pancreas to a Ca 2؉ -signaling pattern that has been associated with premature digestive enzyme activation and the onset of pancreatitis, both of which can be prevented by administration of an intracellular calcium chelator.Alterations in intracellular calcium signaling have previously been reported from an experimental animal model of acute pancreatitis that employs supramaximal secretagogue stimulation for the disease induction (1). Moreover, the spatial and temporal distribution of intracellular calcium signals in response to either physiological or pathological stimuli has been found to be directly related to premature digestive enzyme activation in the pancreas and to acinar cell injury (2-5). Intracellular activation of trypsinogen on the other hand can be completely prevented with agents that interfere with either the uptake of calcium, the maintenance of a calcium gradient across the plasma membrane, or the rapid release of calcium from apical intracellular stores (4, 6). All of these studies indicate clearly that the spatial and temporal distribution of intracellular calcium signals plays a critical role in the early cellular events that precede the onset of pancreatitis. The mechanism, however, that was used to induce acinar cell injury in these studies or in response to which intracellular calcium changes were characterized, supramaximal secretagogue stimulation, is not necessarily an event that is generally involved in the pathogenesis of clinical pancreatitis.In many parts of the world the most common etiological factor associated with acute pancreatitis is gallstone disease. Experimental (7) as well as clinical studies (8, 9) suggest that the onset of gallstone-induced pancreatitis requires migration of the offending stone through the biliary tract and its impaction at the duodenal papilla. Here, at the junction of the common bile duct and the pancreatic duct, the stone can impair the flow of pancreatic secretion or lead to a complete blockage of the pancreatic duct. It is now generally accepted that this impairment of pancreatic secretion (7, 10, 11), rather than a potential reflux of bile into the pancreas (13), represents the critical pathophysiological event for the development gallstoneinduced pancreatitis. To investigate whether this clinically relevant...

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“…(i) The apoprotein alterations held responsible for the platelet-activating properties in the reports cited above [102,108] were not obtained to any significant degree by the prepared hypoxLDL, since under the conditions used by Coleman et al the reactions went on to yield lipid-oxidation products, thereby losing/disturb- [116] , but shed some light on the modifi cation used by Coleman et al The careful measurement of the effect of hypochlorite-modifi ed LDL on intracellular Ca 2+ and membrane Ca-ATPase activity of platelets by Zabe et al [116] clearly reveal a lipoprotein-induced stimulation of Ca-ATPase and, consequently, a decrease of intracellular Ca 2+ in vivo. This is in contrast to the effects of CuoxLDL, which inhibits Ca-ATPase and hence increases intracellular Ca 2+ [117] . Coleman et al's hypochlorite-modifi ed LDL behaves like CuoxLDL with respect to its ability to infl uence intracellular [Ca 2+ ] i , hence at least in this respect, the effects of lipid oxidation are predominant.…”

Section: Hypochlorite Modifi Cation Of Ldlmentioning

confidence: 63%

Modified Low-Density Lipoproteins and High-Density Lipoproteins

Koller

Volf

Gurvitz

et al. 2006

Pathophysiol Haemos Thromb

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It has long been known that the oxidative state of the various plasma lipoproteins modulates platelet aggregability, thereby contributing to atherogenesis. Low-density lipoprotein (LDL), occurring in vivo both in the native and oxidised forms, interacts directly with platelets, by binding to specific receptors. While the identity of the receptors for native LDL and some subfractions of high-density lipoproteins (HDL) remains disputed, apoE-containing HDL₂ binds to LRP8. The nature of these interactions as well as the distinction between candidate receptor proteins was elucidated using covalently modified apolipoproteins, which pointed to the participation of apolipoproteins in high affinity binding. However, the platelet effects initiated by binding of native lipoproteins remain controversial. Some of this ambiguity can be traced to the fact that native LDL inevitably undergoes substantial oxidisation upon modification, including by radiolabelling. The platelet-activating effects provoked by oxidised LDL are irrefutable, but many details remain unknown. The role of CD36 in platelet binding by oxidised LDL is well established, although additional receptors may exist. Much less is known about the interaction of oxidised HDL with platelets, since platelet activation was observed in some, but not all studies. Various frequently applied in vitro oxidation methods produce modified lipoprotein species that may not be relevant in vivo. Based on the reported modifications obtained by in vitro oxidation of LDL, early investigations focused mainly on the formation and the eventual effects of oxidised lipids. More recently, alterations to lipoproteins performed using hypochloric acid and myeloperoxidase redirected the attention to the role of modified apoproteins in triggering platelet responses.

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Oxidized low density lipoprotein inhibits platelet plasma membrane Ca2+-ATPase

Cited by 37 publications

References 29 publications

Modification of Protein Moiety of Human Low Density Lipoprotein by Hypochlorite Generates Strong Platelet Agonist

Modification of Protein Moiety of Human Low Density Lipoprotein by Hypochlorite Generates Strong Platelet Agonist

Early Changes in Pancreatic Acinar Cell Calcium Signaling after Pancreatic Duct Obstruction

Modified Low-Density Lipoproteins and High-Density Lipoproteins

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