Oxidized low density lipoproteins elicit DNA fragmentation of cultured lymphoblastoid cells

AbstractLymphoblastoid cell lines continuously pulsed with mildly oxidized low density lipoproteins, exhibited a significant increase of DNA fragmentation induced by oxidized LDL internalized by cells. DNA fragmentation was associated with an increasing number of morphologically characteristic apoptotic cells simultaneously with the increase of cytotoxicity indexes, and the activation of the poly(ADP-ribose) polymerase, a nuclear enzyme stimulated by DNA strand breaks. The potential involvement of these biochemical and morphological changes in antherogenesis is discussed

Stress-Induced Sphingolipid Signaling: Role of Type-2 Neutral Sphingomyelinase in Murine Cell Apoptosis and Proliferation

International audienceBACKGROUND: Sphingomyelin hydrolysis in response to stress-inducing agents, and subsequent ceramide generation, are implicated in various cellular responses, including apoptosis, inflammation and proliferation, depending on the nature of the different acidic or neutral sphingomyelinases. This study was carried out to investigate whether the neutral Mg(2+)-dependent neutral sphingomyelinase-2 (nSMase2) plays a role in the cellular signaling evoked by TNFalpha and oxidized LDLs, two stress-inducing agents, which are mitogenic at low concentrations and proapoptotic at higher concentrations. METHODOLOGY AND PRINCIPAL FINDINGS: For this purpose, we used nSMase2-deficient cells from homozygous fro/fro (fragilitas ossium) mice and nSMase2-deficient cells reconstituted with a V5-tagged nSMase2. We report that the genetic defect of nSMase2 (in fibroblasts from fro/fro mice) does not alter the TNFalpha and oxidized LDLs-mediated apoptotic response. Likewise, the hepatic toxicity of TNFalpha is similar in wild type and fro mice, thus is independent of nSMase2 activation. In contrast, the mitogenic response elicited by low concentrations of TNFalpha and oxidized LDLs (but not fetal calf serum) requires nSMase2 activation. CONCLUSION AND SIGNIFICANCE: nSMase2 activation is not involved in apoptosis mediated by TNFalpha and oxidized LDLs in murine fibroblasts, and in the hepatotoxicity of TNFalpha in mice, but is required for the mitogenic response to stress-inducing agents

Reactive Carbonyl Species and Protein Lipoxidation in Atherogenesis

Atherosclerosis is a multifactorial disease of medium and large arteries, characterized by the presence of lipid-rich plaques lining the intima over time. It is the main cause of cardiovascular diseases and death worldwide. Redox imbalance and lipid peroxidation could play key roles in atherosclerosis by promoting a bundle of responses, including endothelial activation, inflammation, and foam cell formation. The oxidation of polyunsaturated fatty acids generates various lipid oxidation products such as reactive carbonyl species (RCS), including 4-hydroxy alkenals, malondialdehyde, and acrolein. RCS covalently bind to nucleophilic groups of nucleic acids, phospholipids, and proteins, modifying their structure and activity and leading to their progressive dysfunction. Protein lipoxidation is the non-enzymatic post-translational modification of proteins by RCS. Low-density lipoprotein (LDL) oxidation and apolipoprotein B (apoB) modification by RCS play a major role in foam cell formation. Moreover, oxidized LDLs are a source of RCS, which form adducts on a huge number of proteins, depending on oxidative stress intensity, the nature of targets, and the availability of detoxifying systems. Many systems are affected by lipoxidation, including extracellular matrix components, membranes, cytoplasmic and cytoskeletal proteins, transcription factors, and other components. The mechanisms involved in lipoxidation-induced vascular dysfunction are not fully elucidated. In this review, we focus on protein lipoxidation during atherogenesis

[Neutral lipid storage diseases and ATGL (adipose triglyceride lipase) and CGI-58/ABHD5 (alpha-beta hydrolase domain-containing 5) deficiency: myopathy, ichthyosis, but no obesity]

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Angiogenesis in the atherosclerotic plaque

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Oxidized LDLs trigger endoplasmic reticulum stress and autophagy: prevention by HDLs.

International audienceOxidized LDLs (oxLDLs) induce various cellular dysfunctions potentially implicated in the pathogenesis of atherosclerosis. For instance, toxic concentrations of oxLDLs trigger ER stress, autophagy and apoptosis. High-density lipoproteins (HDLs) counteract several adverse biological effects triggered by oxLDLs. Our recent study reveals that HDLs inhibit the activation of ER stress and of autophagy induced by oxLDLs

Elastin aging and lipid oxidation products in human aorta

Vascular aging is associated with structural and functional modifications of the arteries, and by an increase in arterial wall thickening in the intima and the media, mainly resulting from structural modifications of the extracellular matrix (ECM) components. Among the factors known to accumulate with aging, advanced lipid peroxidation end products (ALEs) are a hallmark of oxidative stress-associated diseases such as atherosclerosis. Aldehydes generated from the peroxidation of polyunsaturated fatty acids (PUFA), (4-hydroxynonenal, malondialdehyde, acrolein), form adducts on cellular proteins, leading to a progressive protein dysfunction with consequences in the pathophysiology of vascular aging. The contribution of these aldehydes to ECM modification is not known. This study was carried out to investigate whether aldehyde-adducts are detected in the intima and media in human aorta, whether their level is increased in vascular aging, and whether elastin fibers are a target of aldehyde-adduct formation. Immunohistological and confocal immunofluorescence studies indicate that 4-HNE-histidine-adducts accumulate in an age-related manner in the intima, media and adventitia layers of human aortas, and are mainly expressed in smooth muscle cells. In contrast, even if the structure of elastin fiber is strongly altered in the aged vessels, our results show that elastin is not or very poorly modified by 4-HNE. These data indicate a complex role for lipid peroxidation and in particular for 4-HNE in elastin homeostasis, in the vascular wall remodeling during aging and atherosclerosis development

Hyperglycemia and glycation in diabetic complications.

International audienceDiabetes mellitus is a multifactorial disease, classically influenced by genetic determinants of individual susceptibility, and by environmental accelerating factors, such as lifestyle. It is considered a major health concern as its incidence is increasing at an alarming rate, and the high invalidating effects of its long-term complications affecting macro- and micro-vasculature, heart, kidney, eye, and nerves. Increasing evidences indicate that hyperglycemia is the initiating cause of tissue damage occurring in diabetes, either through repeated acute changes in cellular glucose metabolism, or through the long-term accumulation of glycated biomolecules and advanced glycation end products (AGE). AGE represent a heterogenous group of chemical products resulting from a nonenzymatic reaction between reducing sugars and proteins, lipids and/or nucleic acids. The glycation process (glucose fixation) affects circulating proteins (serum albumin, lipoprotein, insulin, haemoglobin), while the formation of AGE implicates reactive intermediates such as methylglyoxal. AGE form cross-links on long-lived extracellular matrix proteins, or react with specific receptors RAGE, resulting in oxidative stress and proinflammatory signaling implicated in endothelium dysfunction, arterial stiffening, and microvascular complications. This review summarizes the mechanism of glycation and of AGE formation, and the role of hyperglycemia, AGE and oxidative stress in the pathophysiology of diabetic complications