Chlamydia pneumoniae Augments the Oxidized Low-Density Lipoprotein-Induced Death of Mouse Macrophages by a Caspase-Independent Pathway

ABSTRACT Chlamydia pneumoniae is a common respiratory pathogen that is associated with an increased risk of cardiovascular disease. However, the mechanisms by which C. pneumoniae contributes to cardiovascular disease have not been determined yet. C. pneumoniae infection may accelerate the death of cells within atherosclerotic lesions and contribute to the formation of unstable lesions. To test this hypothesis, the impact of C. pneumoniae infection on the death of lipid-loaded mouse macrophages was investigated. It was observed that RAW 264.7 cells are highly susceptible to the toxic effects of oxidized low-density lipoprotein (LDL) and exhibit markers of cell death within 24 h of treatment with as little as 5 μg/ml oxidized LDL. Subsequent infection with either live C. pneumoniae or heat-killed or UV-inactivated C. pneumoniae at a low multiplicity of infection for 24 to 72 h stimulated both additional binding of annexin V and the uptake of propidium iodide. Thus, C. pneumoniae augments the effects of oxidized LDL on cell death independent of a sustained infection. However, unlike oxidized LDL, C. pneumoniae infection does not activate caspase 3 or induce formation of the mitochondrial transition pore or the fragmentation of DNA, all of which are classical markers of apoptosis. Furthermore, primary bone marrow macrophages isolated from mice deficient in Toll-like receptor 2 (TLR-2) but not TLR-4 are resistant to C. pneumoniae-induced death. These data suggest that C. pneumoniae kills cells by a caspase-independent pathway and that the process is potentially mediated by activation of TLR-2.

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Oxidative stress augments pulmonary hypertension in chronically hypoxic mice overexpressing the oxidized LDL receptor

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00169.2012 ◽

2013 ◽

Vol 305 (2) ◽

pp. H155-H162 ◽

Cited By ~ 24

Author(s):

Sayoko Ogura ◽

Tatsuo Shimosawa ◽

ShengYu Mu ◽

Takashi Sonobe ◽

Fumiko Kawakami-Mori ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Vascular Remodeling ◽

Chronic Hypoxia ◽

Oxidized Ldl ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Ros Generation ◽

Low Density ◽

Ros Production ◽

Oxidized Low Density Lipoprotein

Chronic hypoxia is one of the main causes of pulmonary hypertension (PH) associated with ROS production. Lectin-like oxidized low-density lipoprotein receptor (LOX)-1 is known to be an endothelial receptor of oxidized low-density lipoprotein, which is assumed to play a role in the initiation of ROS generation. We investigated the role of LOX-1 and ROS generation in PH and vascular remodeling in LOX-1 transgenic (TG) mice. We maintained 8- to 10-wk-old male LOX-1 TG mice and wild-type (WT) mice in normoxia (room air) or hypoxia (10% O2 chambers) for 3 wk. Right ventricular (RV) systolic pressure (RVSP) was comparable between the two groups under normoxic conditions; however, chronic hypoxia significantly increased RVSP and RV hypertrophy in LOX-1 TG mice compared with WT mice. Medial wall thickness of the pulmonary arteries was significantly greater in LOX-1 TG mice than in WT mice. Furthermore, hypoxia enhanced ROS production and nitrotyrosine expression in LOX-1 TG mice, supporting the observed pathological changes. Administration of the NADPH oxidase inhibitor apocynin caused a significant reduction in PH and vascular remodeling in LOX-1 TG mice. Our results suggest that LOX-1-ROS generation induces the development and progression of PH.

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Influence of gender on vasomotor effects of oxidized low-density lipoprotein in porcine coronary arteries

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1997.272.6.h2577 ◽

1997 ◽

Vol 272 (6) ◽

pp. H2577-H2583 ◽

Cited By ~ 2

Author(s):

D. A. Cox ◽

M. L. Cohen

Keyword(s):

Coronary Arteries ◽

Oxidized Ldl ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Low Density ◽

Oxidized Low Density Lipoprotein ◽

Male And Female ◽

No Release ◽

Contraction And Relaxation ◽

Coronary Endothelium

This study compared 5-hydroxytryptamine (5-HT)-induced contraction and relaxation in coronary arteries from male and female pigs and compared the vasomotor effects of the atherosclerotic lipoprotein, oxidized low-density lipoprotein (LDL), in these tissues. 5-HT-induced contraction and endothelium-dependent relaxation were similar, as was sodium nitroprusside-induced relaxation, in coronary arteries from male and female pigs. These data suggest that there were no gender-related differences in 5-HT-induced contraction or 5-HT-mediated nitric oxide (NO) release from the coronary endothelium. In contrast, oxidized LDL (100 micrograms/ml) enhanced 5-HT-induced contraction to a greater extent in coronary arteries from male versus female pigs. Because oxidized LDL inhibited 5-HT-induced relaxation similarly in arteries from male and female animals, a greater effect of oxidized LDL on agonist-induced NO release in tissues from male pigs cannot explain the greater effect on 5-HT-induced contraction. Oxidized LDL contracted coronary arteries from males with a greater force than arteries from females when measured from baseline tone, suggesting that oxidized LDL inhibited basal NO release to a greater extent in coronary arteries from male pigs compared with females, an effect that may have participated in the greater enhancement of 5-HT-induced contraction that occurred in arteries from male pigs. These gender-related differences in the vasomotor effects of oxidized LDL may play an important role in the lesser incidence of cardiovascular disease in premenopausal females than in males and may provide insight into the cardioprotective effect of estrogen.

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Low‐Density Lipoprotein Cholesterol Corrected for Lipoprotein(a) Cholesterol, Risk Thresholds, and Cardiovascular Events

Journal of the American Heart Association ◽

10.1161/jaha.119.016318 ◽

2020 ◽

Vol 9 (23) ◽

Author(s):

Peter Willeit ◽

Calvin Yeang ◽

Patrick M. Moriarty ◽

Lena Tschiderer ◽

Stephen A. Varvel ◽

...

Keyword(s):

Cardiovascular Disease ◽

Clinical Care ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Cholesterol Content ◽

Lipoprotein Cholesterol ◽

Low Density ◽

Low Density Lipoprotein Cholesterol ◽

Lipoprotein A ◽

The Impact

Background Conventional "low‐density lipoprotein cholesterol (LDL‐C)" assays measure cholesterol content in both low‐density lipoprotein and lipoprotein(a) particles. To clarify the consequences of this methodological limitation for clinical care, our study aimed to compare associations of “LDL‐C” and corrected LDL‐C with risk of cardiovascular disease and to assess the impact of this correction on the classification of patients into guideline‐recommended LDL‐C categories. Methods and Results Lipoprotein(a) cholesterol content was estimated as 30% of lipoprotein(a) mass and subtracted from “LDL‐C” to obtain corrected LDL‐C values (LDL‐C corr30 ). Hazard ratios for cardiovascular disease (defined as coronary heart disease, stroke, or coronary revascularization) were quantified by individual‐patient‐data meta‐analysis of 5 statin landmark trials from the Lipoprotein(a) Studies Collaboration (18 043 patients; 5390 events; 4.7 years median follow‐up). When comparing top versus bottom quartiles, the multivariable‐adjusted hazard ratio for cardiovascular disease was significant for “LDL‐C” (1.17; 95% CI, 1.05–1.31; P =0.005) but not for LDL‐C corr30 (1.07; 95% CI, 0.93–1.22; P =0.362). In a routine laboratory database involving 531 144 patients, reclassification of patients across guideline‐recommended LDL‐C categories when using LDL‐C corr30 was assessed. In “LDL‐C” categories of 70 to <100, 100 to <130, 130 to <190, and ≥190 mg/dL, significant proportions (95% CI) of participants were reassigned to lower LDL‐C categories when LDL‐C corr30 was used: 30.2% (30.0%–30.4%), 35.1% (34.9%–35.4%), 32.9% (32.6%–33.1%), and 41.1% (40.0%–42.2%), respectively. Conclusions “ LDL‐C” was associated with incident cardiovascular disease only when lipoprotein(a) cholesterol content was included in its measurement. Refinement in techniques to accurately measure LDL‐C, particularly in patients with elevated lipoprotein(a) levels, is warranted to assign risk to the responsible lipoproteins.

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Treatment of macrophages with oxidized low-density lipoprotein increases their intracellular glutathione content

Biochemical Journal ◽

10.1042/bj2780429 ◽

1991 ◽

Vol 278 (2) ◽

pp. 429-434 ◽

Cited By ~ 58

Author(s):

V M Darley-Usmar ◽

A Severn ◽

V J O'Leary ◽

M Rogers

Keyword(s):

Oxidized Ldl ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Human Monocyte ◽

Cell Types ◽

Oxidative Modification ◽

Glutathione Depletion ◽

Lipid Phase ◽

Low Density ◽

Oxidized Low Density Lipoprotein

Macrophages derived from the human monocyte cell line THP-1 or isolated from the peritoneum of C3H/HEJ mice were incubated with oxidized low-density lipoprotein (LDL) and the total glutathione content (oxidized plus reduced) was measured. An initial depletion of glutathione was followed by an increase, such that after a period of 24 h the glutathione content has approximately doubled. This response required the oxidation of the lipid phase of the LDL molecule, since both native LDL and acetylated LDL had little effect on glutathione levels. The response of the cells to oxidized LDL was dependent on the extent of oxidative modification of the protein. It was also found that 4-hydroxynonenal had a similar effect on THP-1 cells, and we suggest that this or other aldehydes present in oxidized LDL causes the induction of glutathione synthesis in response to an initial oxidative stress and consequent glutathione depletion. In addition, we found that both cell types possess transferases and peroxidases capable of detoxifying aldehydes and peroxides. However, treatment of cells with oxidized LDL or 4-hydroxynonenal for a period of 24 h had no effect on the activities of these enzymes.

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Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1): a crucial driver of atherosclerotic cardiovascular disease

European Heart Journal ◽

10.1093/eurheartj/ehaa770 ◽

2020 ◽

Author(s):

Alexander Akhmedov ◽

Tatsuya Sawamura ◽

Chu-Huang Chen ◽

Simon Kraler ◽

Daria Vdovenko ◽

...

Keyword(s):

Oxidized Ldl ◽

Low Density Lipoprotein ◽

Ldl Receptor ◽

Density Lipoprotein ◽

Basic Research ◽

Plaque Formation ◽

Atherosclerotic Cardiovascular Disease ◽

Low Density ◽

Oxidized Low Density Lipoprotein ◽

Atheromatous Plaques

Abstract Cardiovascular diseases (CVDs), specifically lipid-driven atherosclerotic CVDs, remain the number one cause of death worldwide. The lectin-like oxidized low-density lipoprotein (LDL) receptor-1 (LOX-1), a scavenger receptor that promotes endothelial dysfunction by inducing pro-atherogenic signalling and plaque formation via the endothelial uptake of oxidized LDL (oxLDL) and electronegative LDL, contributes to the initiation, progression, and destabilization of atheromatous plaques, eventually leading to the development of myocardial infarction and certain forms of stroke. In addition to its expression in endothelial cells, LOX-1 is expressed in macrophages, cardiomyocytes, fibroblasts, dendritic cells, lymphocytes, and neutrophils, further implicating this receptor in multiple aspects of atherosclerotic plaque formation. LOX-1 holds promise as a novel diagnostic and therapeutic target for certain CVDs; therefore, understanding the molecular structure and function of LOX-1 is of critical importance. In this review, we highlight the latest scientific findings related to LOX-1, its ligands, and their roles in the broad spectrum of CVDs. We describe recent findings from basic research, delineate their translational value, and discuss the potential of LOX-1 as a novel target for the prevention, diagnosis, and treatment of related CVDs.

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