Conformational changes of apoB-100 in SMase-modified LDL mediate formation of large aggregates at acidic pH

Sneck, Mia; Nguyen, Su Duy; Pihlajamaa, Tero; Yohannes, Gebrenegus; Riekkola, Marja‐Liisa; Milne, Ross W.; Kovanen, Petri T.; Öörni, Katariina

doi:10.1194/jlr.m023218

Cited by 40 publications

(51 citation statements)

References 48 publications

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“…This result agrees with studies by Oorni and colleagues showing that mildly acidic pH promotes LDL fusion by sphingomyelinase at near-physiologic temperatures (Ref. 47 and references therein). Taken rate of thermal denaturation ( Fig.…”

Section: Effects Of Ldl Concentration Particle Size and Ph On The Rsupporting

confidence: 83%

“…4 interactions among LDL subclasses and suggests that they can fuse with each other. Taken together with a similar nonadditive behavior of human HDL subclasses during heat denaturation ( 46 ) and with the demonstrated ability of HDL or its major protein apoA-I, to inhibit LDL aggregation and fusion ( 29,(47)(48)(49), this result indicates that different lipoprotein classes and subclasses interact with each other during fusion.…”

Section: Effects Of Ldl Concentration Particle Size and Ph On The Rmentioning

confidence: 86%

“…This may include extensive lipolysis of phospholipids, hydrolysis of apoB with release of proteolytic fragments, and chemical or thermal denaturation ( 9-16, 29-32, 47-49 ). Some of these perturbations have been proposed to involve conformational changes in apoB, particularly its N-and C-terminal domains ( 28,47 ). The enormous size of apoB prompts us to hypothesize that its structure is kinetically trapped by both protein-lipid and protein-protein interactions.…”

Section: Effects Of Ldl Concentration Particle Size and Ph On The Rmentioning

confidence: 99%

“…Destabilization of LDL at mildly acidic pH may result, in part, from the reduced electrostatic repulsion between the particles upon reduction in their net charge below pH 7 ( 50 ). This destabilization likely contributes to LDL retention in the mildly acidic anaerobic environment of the atherosclerotic plaques ( 47,(60)(61)(62) and helps explain why LDL accumulation during atherogenesis starts in the deep areas of arterial thickening that have lowest pH ( 47,63 ). In addition, destabilization of LDL at acidic pH is expected to promote their lysosomal degradation during normal catabolism.…”

Section: Effect Of Ph: Relevance To Acidic Conditions In Atheroscleromentioning

confidence: 99%

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Kinetic analysis of thermal stability of human low density lipoproteins: a model for LDL fusion in atherogenesis

Gantz

Herscovitz

et al. 2012

Journal of Lipid Research

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of LDL cholesterol and, particularly, apoB are the strongest predictors of atherosclerosis and its causative agents ( 3 ). In atherosclerosis, LDL lipids are deposited in the arterial intima; according to the response-to-retention paradigm ( 4, 5 ), LDL retention by the arterial matrix proteoglycans triggers a cascade of pro-atherogenic events culminating in formation of atherosclerotic plaque ( 6-8 ). These events include biochemical modifi cations of LDL, such as oxidation and/or hydrolysis by the resident proteases and lipases, e.g., phospholipase A 2 and sphingomyelinase, which can reduce LDL affi nity for the LDL receptor, increase LDL affi nity for the proteoglycans, and promote LDL fusion (7)(8)(9)(10)(11)(12)(13)(14). In addition, ionic interactions with proteoglycans reduce LDL stability and promote their fusion and rupture (i.e., release of core lipids) ( 15 ). Fusion of lipoproteins prevents their exit from the arterial intima and thereby augments their further modifi cations, enhances LDL uptake by the arterial macrophages, and initiates the formation of atherosclerotic lesions ( 9, 16 ). Therefore, the pro-atherogenic potential of LDL is thought to be linked to their ability to fuse ( 9,10,17 ). Dissecting the pathogenic pathway of LDL fusion and identifying key factors that promote or inhibit this pathway can help obtain new therapeutic targets for atherosclerosis.Structural analysis of intact and modifi ed LDL has been limited to low resolution ( у 16 Å) by the large size and hydrophobicity of apoB and by LDL heterogeneity ( 1,(18)(19)(20)(21). Human plasma LDL consist of subclasses differing Abstract Fusion of modifi ed LDL in the arterial wall promotes atherogenesis. Earlier we showed that thermal denaturation mimics LDL remodeling and fusion, and revealed kinetic origin of LDL stability. Here we report the fi rst quantitative analysis of LDL thermal stability. Turbidity data show sigmoidal kinetics of LDL heat denaturation, which is unique among lipoproteins, suggesting that fusion is preceded by other structural changes. High activation energy of denaturation, E a = 100 ± 8 kcal/mol, indicates disruption of extensive packing interactions in LDL. Size-exclusion chromatography, nondenaturing gel electrophoresis, and negativestain electron microscopy suggest that LDL dimerization is an early step in thermally induced fusion. Monoclonal antibody binding suggests possible involvement of apoB N-terminal domain in early stages of LDL fusion. LDL fusion accelerates at pH < 7, which may contribute to LDL retention in acidic atherosclerotic lesions. Fusion also accelerates upon increasing LDL concentration in near-physiologic range, which likely contributes to atherogenesis. Thermal stability of LDL decreases with increasing particle size, indicating that the pro-atherogenic properties of small dense LDL do not result from their enhanced fusion. Our work provides the fi rst kinetic approach to measuring LDL stability and suggests that lipid-lowering therapies that reduce LDL concentration but increase t...

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Section: Effects Of Ldl Concentration Particle Size and Ph On The Rsupporting

confidence: 83%

Section: Effects Of Ldl Concentration Particle Size and Ph On The Rmentioning

confidence: 86%

Section: Effects Of Ldl Concentration Particle Size and Ph On The Rmentioning

confidence: 99%

Section: Effect Of Ph: Relevance To Acidic Conditions In Atheroscleromentioning

confidence: 99%

See 2 more Smart Citations

Kinetic analysis of thermal stability of human low density lipoproteins: a model for LDL fusion in atherogenesis

Gantz

Herscovitz

et al. 2012

Journal of Lipid Research

View full text Add to dashboard Cite

show abstract

“…Furthermore, treatment of LDL with human recombinant secretory ASM in vitro induces the formation of lesion-like LDL aggregates. Sneck et al [3] showed that sphingomyelin hydrolysis induces exposure of proteasesensitive sites of apoB-100, whose interactions govern subsequent particle aggregation. They found that supersized LDL aggregates could contribute to the retention of LDL lipids in acidic areas of atherosclerosis-susceptible sites in the arterial intima.…”

mentioning

confidence: 99%