Lysosomal oxidation of LDL alters lysosomal pH, induces senescence, and increases secretion of pro-inflammatory cytokines in human macrophages

Ahmad, Feroz; Leake, David S.

doi:10.1194/jlr.m088245

Cited by 44 publications

(36 citation statements)

References 78 publications

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“…Indeed, the lysosomal acidic environment increases the solubility of iron facilitating oxidation (Satchell and Leake, 2012). Furthermore, it has been demonstrated that LDL can be oxidized within the lysosomes of macrophages (Lamb and Leake, 1994;Ojo and Leake, 2018;Ahmad and Leake, 2019). In contrast, when LDL are incubated with copper at acidic pH its oxidation is delayed (Morgan and Leake, 1995), indicating that LDL oxidation by copper within lysosomes is unlikely to occur.…”

Section: Lysosomal Iron Metabolismmentioning

confidence: 99%

Lysosome (Dys)function in Atherosclerosis—A Big Weight on the Shoulders of a Small Organelle

Marques

Ramos

Machado-Oliveira

et al. 2021

Front. Cell Dev. Biol.

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Atherosclerosis is a progressive insidious chronic disease that underlies most of the cardiovascular pathologies, including myocardial infarction and ischemic stroke. The malfunctioning of the lysosomal compartment has a central role in the etiology and pathogenesis of atherosclerosis. Lysosomes are the degradative organelles of mammalian cells and process endogenous and exogenous substrates in a very efficient manner. Dysfunction of these organelles and consequent inefficient degradation of modified low-density lipoproteins (LDL) and apoptotic cells in atherosclerotic lesions have, therefore, numerous deleterious consequences for cellular homeostasis and disease progression. Lysosome dysfunction has been mostly studied in the context of the inherited lysosomal storage disorders (LSDs). However, over the last years it has become increasingly evident that the consequences of this phenomenon are more far-reaching, also influencing the progression of multiple acquired human pathologies, such as neurodegenerative diseases, cancer, and cardiovascular diseases (CVDs). During the formation of atherosclerotic plaques, the lysosomal compartment of the various cells constituting the arterial wall is under severe stress, due to the tremendous amounts of lipoproteins being processed by these cells. The uncontrolled uptake of modified lipoproteins by arterial phagocytic cells, namely macrophages and vascular smooth muscle cells (VSMCs), is the initial step that triggers the pathogenic cascade culminating in the formation of atheroma. These cells become pathogenic “foam cells,” which are characterized by dysfunctional lipid-laden lysosomes. Here, we summarize the current knowledge regarding the origin and impact of the malfunctioning of the lysosomal compartment in plaque cells. We further analyze how the field of LSD research may contribute with some insights to the study of CVDs, particularly how therapeutic approaches that target the lysosomes in LSDs could be applied to hamper atherosclerosis progression and associated mortality.

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Section: Lysosomal Iron Metabolismmentioning

confidence: 99%

Lysosome (Dys)function in Atherosclerosis—A Big Weight on the Shoulders of a Small Organelle

Marques

Ramos

Machado-Oliveira

et al. 2021

Front. Cell Dev. Biol.

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“…Intrinsically related with this is the modification of the lysosomal pH that alters the activity of the majority of the lysosomal enzymes [ 162 ] and compromises the substrates of autophagic degradation as well as the endocytic cargo in senescent lysosomes [ 163 , 164 , 165 ]. Most interestingly, it has been recently shown that lysosomal oxidation of aggregated LDL alters the lysosomal pH, inducing cellular senescence and increasing secretion of pro-inflammatory cytokines in human macrophages [ 166 ]. These findings reinforce once more the active contribution of senescent lysosomes and the process of cellular senescence for atherogenesis.…”

Section: Cellular Organelles In Senescent Cellsmentioning

confidence: 99%

Cell Senescence, Multiple Organelle Dysfunction and Atherosclerosis

Machado-Oliveira

Ramos

Marques

et al. 2020

Cells

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Atherosclerosis is an age-related disorder associated with long-term exposure to cardiovascular risk factors. The asymptomatic progression of atherosclerotic plaques leads to major cardiovascular diseases (CVD), including acute myocardial infarctions or cerebral ischemic strokes in some cases. Senescence, a biological process associated with progressive structural and functional deterioration of cells, tissues and organs, is intricately linked to age-related diseases. Cell senescence involves coordinated modifications in cellular compartments and has been demonstrated to contribute to different stages of atheroma development. Senescence-based therapeutic strategies are currently being pursued to treat and prevent CVD in humans in the near-future. In addition, distinct experimental settings allowed researchers to unravel potential approaches to regulate anti-apoptotic pathways, facilitate excessive senescent cell clearance and eventually reverse atherogenesis to improve cardiovascular function. However, a deeper knowledge is required to fully understand cellular senescence, to clarify senescence and atherogenesis intertwining, allowing researchers to establish more effective treatments and to reduce the cardiovascular disorders’ burden. Here, we present an objective review of the key senescence-related alterations of the major intracellular organelles and analyze the role of relevant cell types for senescence and atherogenesis. In this context, we provide an updated analysis of therapeutic approaches, including clinically relevant experiments using senolytic drugs to counteract atherosclerosis.

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“…the large clinical trials of a-tocopherol were ineffective. It would be desirable to conduct clinical trials of antioxidants that accumulate in lysosomes and inhibit the oxidation of LDL at acidic pH, such as cysteamine [22][23][24][25].…”

Section: Aàtoc O þX ! Nonradical Productmentioning

confidence: 99%

“…We have shown previously that LDL can be oxidised by iron in the lysosomes of macrophages [21] and that this causes the secretion of inflammatory cytokines [22]. The antioxidant cysteamine, which accumulates in lysosomes, inhibits the lysosomal oxidation of LDL [22][23][24][25] and decreases atherosclerosis in LDL receptor-deficient mice [25].…”

Section: Introductionmentioning

confidence: 98%

Effect of vitamin E on low density lipoprotein oxidation at lysosomal pH

Alboaklah

Leake

2020

Free Radical Research

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Many cholesterol-laden foam cells in atherosclerotic lesions are macrophages and much of their cholesterol is present in their lysosomes and derived from low density lipoprotein (LDL). LDL oxidation has been proposed to be involved in the pathogenesis of atherosclerosis. We have shown previously that LDL can be oxidised in the lysosomes of macrophages. a-Tocopherol has been shown to inhibit LDL oxidation in vitro, but did not protect against cardiovascular disease in large clinical trials. We have therefore investigated the effect of a-tocopherol on LDL oxidation at lysosomal pH (about pH 4.5). LDL was enriched with a-tocopherol by incubating human plasma with a-tocopherol followed by LDL isolation by ultracentrifugation. The a-tocopherol content of LDL was increased from 14.4 ± 0.2 to 24.3 ± 0.3 nmol/mg protein. LDL oxidation was assessed by measuring the formation of conjugated dienes at 234 nm and oxidised lipids (cholesteryl linoleate hydroperoxide and 7-ketocholesterol) by HPLC. As expected, LDL enriched with a-tocopherol was oxidised more slowly than control LDL by Cu 2þ at pH 7.4, but was not protected against oxidation by Cu 2þ or Fe 3þ or a low concentration of Fe 2þ at pH 4.5 (it was sometimes oxidised faster by a-tocopherol with Cu 2þ or Fe 3þ at pH 4.5). a-Tocopherol-enriched LDL reduced Cu 2þ and Fe 3þ into the more pro-oxidant Cu þ and Fe 2þ faster than did control LDL at pH 4.5. These findings might help to explain why the large clinical trials of a-tocopherol did not protect against cardiovascular disease.

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Lysosomal oxidation of LDL alters lysosomal pH, induces senescence, and increases secretion of pro-inflammatory cytokines in human macrophages

Cited by 44 publications

References 78 publications

Lysosome (Dys)function in Atherosclerosis—A Big Weight on the Shoulders of a Small Organelle

Lysosome (Dys)function in Atherosclerosis—A Big Weight on the Shoulders of a Small Organelle

Cell Senescence, Multiple Organelle Dysfunction and Atherosclerosis

Effect of vitamin E on low density lipoprotein oxidation at lysosomal pH

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