Characterization of apoptotic macrophages in atheromatous tissue of humans and heritable hyperlipidemic rabbits

Kinscherf, Ralf; Wagner, Martin; Kamencic, Huse; Bonaterra, Gabriel A.; Hou, Dongming; R, Schiele; Deigner, Hans‐Peter; Metz, J.

doi:10.1016/s0021-9150(99)00037-4

Cited by 47 publications

(43 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Binding of oxidized LDL leads to the activation of monocytes and macrophages and stimulates the expression of Mn-SOD which, in turn, increases the concentration of hydrogen peroxide by perturbing the steadystate levels of ROS (305,306,308). This process is associated with massive macrophage apoptosis and contributes thereby to the formation of the atherosclerotic lesions (309,461). The process may be further enhanced by cytokines and other factors such as TNF, interleukin-1␤, angiotensin II, and interferon-␥, which induce superoxide production by the membrane-bound NADPH oxidase in endothelial cells (136,210,396,424).…”

Section: K Atherosclerosismentioning

confidence: 99%

Free Radicals in the Physiological Control of Cell Function

Dröge

2002

Physiological Reviews

8,447

5,836

View full text Add to dashboard Cite

At high concentrations, free radicals and radical-derived, nonradical reactive species are hazardous for living organisms and damage all major cellular constituents. At moderate concentrations, however, nitric oxide (NO), superoxide anion, and related reactive oxygen species (ROS) play an important role as regulatory mediators in signaling processes. Many of the ROS-mediated responses actually protect the cells against oxidative stress and reestablish “redox homeostasis.” Higher organisms, however, have evolved the use of NO and ROS also as signaling molecules for other physiological functions. These include regulation of vascular tone, monitoring of oxygen tension in the control of ventilation and erythropoietin production, and signal transduction from membrane receptors in various physiological processes. NO and ROS are typically generated in these cases by tightly regulated enzymes such as NO synthase (NOS) and NAD(P)H oxidase isoforms, respectively. In a given signaling protein, oxidative attack induces either a loss of function, a gain of function, or a switch to a different function. Excessive amounts of ROS may arise either from excessive stimulation of NAD(P)H oxidases or from less well-regulated sources such as the mitochondrial electron-transport chain. In mitochondria, ROS are generated as undesirable side products of the oxidative energy metabolism. An excessive and/or sustained increase in ROS production has been implicated in the pathogenesis of cancer, diabetes mellitus, atherosclerosis, neurodegenerative diseases, rheumatoid arthritis, ischemia/reperfusion injury, obstructive sleep apnea, and other diseases. In addition, free radicals have been implicated in the mechanism of senescence. That the process of aging may result, at least in part, from radical-mediated oxidative damage was proposed more than 40 years ago by Harman ( J Gerontol 11: 298–300, 1956). There is growing evidence that aging involves, in addition, progressive changes in free radical-mediated regulatory processes that result in altered gene expression.

show abstract

Section: K Atherosclerosismentioning

confidence: 99%

Free Radicals in the Physiological Control of Cell Function

Dröge

2002

Physiological Reviews

8,447

5,836

View full text Add to dashboard Cite

show abstract

“…44 Furthermore, the appearance of p53 and iNOS in apoptotic macrophages is established in human atherosclerotic lesions. 66 Moreover, a positive correlation between NO formation and apoptosis is also implied for articular cartilage samples from humans with osteoarthritis 67,68 or for the occurrence of human lupus nephritis. 69 Generally, it appears that NO is endowed with the capability to initiate apoptosis in cellular systems, co-cultures, and in vivo.…”

Section: Lessons From Disease Statesmentioning

confidence: 99%

Nitric oxide (NO): an effector of apoptosis

1999

View full text Add to dashboard Cite

It is appreciated that the production of nitric oxide (NO) from Larginine metabolism is an essential determinate of the innate immune system, important for nonspecific host defense, as well as tumor and pathogen killing. Cytotoxicity as a result of a substantial NO-formation is established to initiate apoptosis, characterized by upregulation of the tumor suppressor p53, changes in the expression of pro-and anti-apoptotic Bcl-2 family members, cytochrome c relocation, activation of caspases, chromatin condensation, and DNA fragmentation. Proof for the involvement of NO was demonstrated by blocking adverse effects by NO-synthase inhibition. However, NOtoxicity is not a constant value and NO may achieve cell protection as well. In part this is understood by transcription and translation of protective proteins, such as cyclooxygenase-2. Alternatively, protection may result as a consequence of a diffusion controlled NO/O 2 7 (superoxide) interaction that redirects the apoptotic initiating activity of NO towards protection. NO is endowed with the unique ability to initiate and to block apoptosis, depending on multiple variables that exist to be elucidated. The crosstalk between cell destructive and protective signaling pathways under the modulatory influence of NO will determine the impact of NO in apoptotic cell death and survival.

show abstract

“…Indeed, previous studies have found that apoptotic macrophages in human atherosclerotic plaques are activated, express antigen, and are oxidatively stressed. 13 Thus, local ROS generation may induce both macrophage growth arrest and apoptosis. The recent view of macrophages in atherosclerosis hypothesizes that activated macrophages promote plaque instability by secretion of metalloproteinases that degrade matrix and collagen.…”

Section: Oxidative Damage To Dnamentioning

confidence: 99%

Reactive Oxygen Species and Death

Bennett

2001

Circulation Research

View full text Add to dashboard Cite

R eactive oxygen species (ROS) (eg, superoxide, peroxide, and hydroxyl radicals) and reactive nitrogen species (eg, peroxynitrite) are generated in both atherogenesis and advanced atherosclerosis, 1 particularly by macrophages. 2 ROS have many actions, including oxidative modification of LDL and oxidative damage of DNA. Oxidative Modification of LDLAlthough LDL is essential to deliver cholesterol to tissues, increased LDL cholesterol is associated with increased risk of cardiovascular disease. Oxidative modification of LDL promotes recruitment and retention of monocytes 3 with formation of fatty streaks, the earliest lesions in atherosclerosis. 4 Both macrophages and vascular smooth muscle cells (VSMCs) bind oxidized LDL via specific scavenger receptors, 5,6 forming foam cells. Macrophage foam cells contain potent oxidant-generating systems that target lipids, including myeloperoxidase, nitric oxide (NO) synthase, and 15-lipoxygenase, allowing increased recognition and uptake by macrophages, creating a positive feedback loop. Oxidative Damage to DNAROS also induce oxidative damage of DNA, including strand breaks and base and nucleotide modifications, particularly in sequences with high guanosine content. 7 Oxidative modification induces a robust repair response, characterized by excision of modified bases and nucleotides. Double-stranded DNA breaks also activate DNA repair enzymes, including ATM (mutated in ataxia telangiectasia) and ATR (ATMrelated kinase). Both ATM and ATR directly phosphorylate and activate specific checkpoint kinases, such as chk2 and hCDS1, with subsequent phosphorylation of the tumor suppressor gene p53.p53 is the commonest mutation in human cancer and has a major role in genomic surveillance. p53 stimulates base excision repair 8 but also coordinates the cell's response to damage. p53 phosphorylation stabilizes the protein and increases its transcriptional activity, inducing both growth arrest and apoptosis. Thus, ROS-induced DNA damage leads to p53 activation, and growth arrest and apoptosis after DNA damage depend partly on p53.Although the presence of ROS within the atherosclerotic plaque is not disputed, the major target cells of ROS in vivo are unclear. In particular, ROS induce toxicity in many vascular cell types in culture. 9 In view of this, the study by Martinet et al 10 in this issue of Circulation Research provides important insights into the role of ROS in atherogenesis and plaque stability. These investigators demonstrated that cholesterol feeding of rabbits induces oxidative damage in plaques, manifested by expression of 8-oxo-G, an oxidative modification of guanine residues in DNA, 7 DNA strand breaks, and apoptosis. A graded response was seen, the percentage of cells expressing markers being 8-oxoGϾstrand breaksϾapoptosis, consistent with fewer cells demonstrating increasing degrees of oxidative damage. These changes were associated with expression of DNA repair enzymes and p53. Importantly, these markers of oxidative damage were rapidly reversible with cholesterol loweri...

show abstract

Characterization of apoptotic macrophages in atheromatous tissue of humans and heritable hyperlipidemic rabbits

Cited by 47 publications

References 37 publications

Free Radicals in the Physiological Control of Cell Function

Free Radicals in the Physiological Control of Cell Function

Nitric oxide (NO): an effector of apoptosis

Reactive Oxygen Species and Death

Contact Info

Product

Resources

About