Apolipoprotein A-I mimetic peptide 4F blocks sphingomyelinase-induced LDL aggregation

Nguyen, Su Duy; Javanainen, Matti; Rissanen, Sami; Zhao, Hongxia; Huusko, Jenni; Kivelä, Annukka M.; Ylä‐Herttuala, Seppo; Navab, Mohamad; Fogelman, Alan M.; Vattulainen, Ilpo; Kovanen, Petri T.; Öörni, Katariina

doi:10.1194/jlr.m059485

Cited by 23 publications

(19 citation statements)

References 60 publications

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“…In line with this hypothesis, clinical evidence suggests that high levels of HDL-C not always are atheroprotective, and instead may mark pro-inflammatory/pro-atherogenic features. On the other hand, small peptides that mimic the function of apoA-I render HDL less inflammatory [27], promote macrophage reverse cholesterol transport [231] and inhibit LDL aggregation [232], and were found to be effective in several animal models of disease [233][234][235][236][237]. These observations also reveal the limitations of measurements based only on the determination of HDL-C levels.…”

Section: Discussionmentioning

confidence: 97%

Biological Consequences of Dysfunctional HDL

Pirillo

Catapano

Norata

2019

CMC

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Epidemiological studies have suggested an inverse correlation between high density lipoprotein (HDL) cholesterol levels and the risk of cardiovascular disease. HDLs promote reverse cholesterol transport (RCT) and possess several putative atheroprotective functions, associated to the anti-inflammatory, anti-thrombotic and anti-oxidant properties as well as to the ability to support endothelial physiology. The assumption that increasing HDL-C levels would be beneficial on cardiovascular disease (CVD), however, has been questioned as, in most clinical trials, HDL-C-raising therapies did not result in improved cardiovascular outcomes. These findings, together with the observations from Mendelian randomization studies showing that polymorphisms mainly or solely associated with increased HDL-C levels did not decrease the risk of myocardial infarction, shift the focus from HDL-C levels toward HDL functional properties. Indeed, HDL from atherosclerotic patients not only exhibit impaired atheroprotective functions but also acquire pro-atherogenic properties and are referred to as "dysfunctional" HDL; this occurs even in the presence of normal or elevated HDL-C levels. Pharmacological approaches aimed at restoring HDL functions may therefore impact more significantly on CVD outcome than drugs used so far to increase HDL-C levels. Aims of this review is to discuss the pathological conditions leading to the formation of dysfunctional HDL and their role in atherosclerosis and beyond.

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Section: Discussionmentioning

confidence: 97%

Biological Consequences of Dysfunctional HDL

Pirillo

Catapano

Norata

2019

CMC

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“…These include limiting LDL oxidation and aggregation to reduce monocyte adhesion to proteoglycans and improving HDL function by increasing pre-b HDL, decreasing lipid hydroperoxides in HDL, and enhancing anti-inflammatory properties. 38,94,95 Amphiphilic L-4F quells inflammation by scavenging oxidized phospholipids and fatty acid hydroperoxides that might otherwise partition into cellular membranes. 37,38,96 Our initial expectation was that L-4F would sequester oxidized lipids and remove them into the circulation.…”

Section: Discussionmentioning

confidence: 99%

Apolipoprotein A-I Mimetic Peptide L-4F Removes Bruch's Membrane Lipids in Aged Nonhuman Primates

Rudolf

Curcio

Schlötzer‐Schrehardt

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Multiple evidence lines support Bruch's membrane lipid deposition as a major precursor of soft drusen and age-related macular degeneration as including a potentially treatable atherosclerosis-like progression in the subretinal pigment epithelium (RPE)-basal lamina space. We evaluated the effect of anti-inflammatory, antiatherogenic peptide L-4F on Bruch's membrane of aged nonhuman primates in a dose-escalating study. METHODS. Macaca fascicularis ‡20 years of age evaluated by color fundus photography and optical coherence tomography received monocular intravitreal injections of L-4F (n ¼ 7) or a placebo-scrambled peptide (n ¼ 2) in 6 doses of 25 to 175 lg over 6 months. Eyes were processed for detection and masked semiquantitative assessment of macular Bruch's membrane neutral lipid (oil red O staining), esterified cholesterol (filipin histochemistry), membrane attack complex (immunofluorescence), and paramacular thickness (transmission electron microscopy). RESULTS. Bruch's membrane neutral lipid, esterified cholesterol, and membrane attack complex were cleared and ultrastructure was improved in L-4F-injected eyes, compared to placebo-injected eyes. Fellow eyes were also affected to the same degree as the injected eyes. Punctate yellow fundus lesions without corresponding RPE elevations on optical coherence tomography correlated to RPE lipoidal degeneration (engorgement with lipid droplets), which was unchanged by this treatment. CONCLUSIONS. Clinical-stage apolipoprotein A-I mimetic peptide L-4F, delivered intravitreally in repeated doses, produced a substantial pharmacologic reduction of Bruch's membrane lipid and restoration of ultrastructure in a nonhuman primate model that exhibits an important precursor of soft drusen, if not soft drusen themselves.

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“…Along these lines, the apoA-I mimetic peptide 4F was recently shown to block SMaseinduced LDL aggregation and the increase in binding of the modified LDL particles to human aortic proteoglycans. (59) In contrast, abnormal HDL or apoA-I within the arterial wall may have adverse effects. (53,(60)(61)(62) Using our extensive knowledge of the pathogenesis of atherosclerosis, we can now reclassify nearly all epidemiologic risk factors into causative agents, exacerbating factors and bystander phenomena.…”

Section: Lipoproteins Apolipoproteins and Atherosclerosismentioning

confidence: 99%

Advanced in Molecular Mechanisms of Atherosclerosis: From Lipids to Inflammation

2018

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BACKGROUND: Atherosclerosis is a leading cause of vascular disease worldwide. During the past several decades, landmark discoveries in the field of vascular biology have evolved our understanding of the biology of blood vessels and the pathobiology of local and systemic vascular disease states and have led to novel disease-modifying therapies for patients. This review is made to understand the molecular mechanism of atherosclerosis for these future therapies.CONTENT: Advances in molecular biology and -omics technologies have facilitated in vitro and in vivo studies which revealed that blood vessels regulate their own redox milieu, metabolism, mechanical environment, and phenotype, in part, through complex interactions between cellular components of the blood vessel wall and circulating factors. Dysregulation of these carefully orchestrated homeostatic interactions has also been implicated as the mechanism by which risk factors for cardiopulmonary vascular disease lead to vascular dysfunction, structural remodeling and, ultimately, adverse clinical events.SUMMARY: Atherosclerosis is a heterogeneous disease, despite a common initiating event of apoB-lipoproteins. Despite of acute thrombotic complications, an adequate resolution response is mounted, where efferocytosis prevents plaque necrosis and a reparative scarring response (the fibrous cap) prevents plaque disruption. However, a small percentage of developing atherosclerotic lesions cannot maintain an adequate resolution response, which leading to the formation of clinically dangerous plaques that can trigger acute lumenal thrombosis and tissue ischemiaand infarction.KEYWORDS: atherosclerosis, oxidative stress, inflammation, efferocytosis, foam cells, thrombosis

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Apolipoprotein A-I mimetic peptide 4F blocks sphingomyelinase-induced LDL aggregation

Cited by 23 publications

References 60 publications

Biological Consequences of Dysfunctional HDL

Biological Consequences of Dysfunctional HDL

Apolipoprotein A-I Mimetic Peptide L-4F Removes Bruch's Membrane Lipids in Aged Nonhuman Primates

Advanced in Molecular Mechanisms of Atherosclerosis: From Lipids to Inflammation

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