Chlamydia pneumoniae Alters Mildly Oxidized Low‐Density Lipoprotein–Induced Cell Death in Human Endothelial Cells, Leading to Necrosis Rather Than Apoptosis

INSERM U466, Institut Louis Bugnard, Centre Hospitalier Universitaire Rangueil and Universite Paul Sabatier, Toulouse, France.
The Journal of Infectious Diseases (Impact Factor: 6). 02/2006; 193(1):136-45. DOI: 10.1086/498617
Source: PubMed


Atherosclerosis is characterized by oxidative stress that induces lipid and protein oxidation in the vascular wall. Oxidized low-density lipoproteins (oxLDLs) are present in lesions, and one of their actions is to induce apoptosis or necrosis in vascular cells. A role for Chlamydia pneumoniae in atherosclerosis has been proposed, but the mechanisms involved remain largely unknown.
The in vitro effect of C. pneumoniae infection on apoptosis induced by mildly oxidized LDLs (moxLDLs) in human endothelial cells was studied.
Infection inhibited apoptosis, as was demonstrated by a decrease in such apoptotic features as cytochrome c release, caspase activity, 89-kilodalton poly(ADP-ribose) polymerase (PARP) fragment formation, nuclear condensation and fragmentation, and DNA fragmentation. However, the inhibition of apoptosis did not favor cell survival, because infection promoted cell death with necrotic features, as was illustrated by an increase in lactate dehydrogenase release, an enhancement of necrotic cellular morphological characteristics, and generation of low-molecular-mass PARP fragments. The increase in occurrence of necrosis-like cell death was correlated with a strong increase in intracellular reactive oxygen species (ROS) concentration. Vitamin E inhibited ROS production and promoted cell survival, underscoring the involvement of ROS in cell death induced by the combination of C. pneumoniae and moxLDLs.
C. pneumoniae infection enhances the inflammatory action of oxLDLs in the vascular wall, leading to cell necrosis rather than apoptosis.

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    • "Antigen Reference Autoantigens Oxidised low-density lipoprotein (LDL) [21] [22] [23] Beta2glycoprotein1 (beta2GP1) [24] [25] [26] Lipoprotein a (LP(a)) [27] Lipoprotein-lipase (LPL) [28] Advanced glycation-end products (AGE) [29] Heat-shock proteins [30] [31] Collagen [32] [33] [34] Fibrinogen [35] Microbial antigens Porphyromonas gingivalis [36] [37] Chlamydia pneumoniae [38] [39] [40] [41] [42] [43] [44] [45] [46] [47] [48] [49] Bacteroides forsynthus [36] Streptococcus mutans [36] [37] [50] Helicobacter pylori [51] [52] [53] [54] [55] [56] [57] [58] [59] [60] [61] [62] [63] [64] Echerichia coli [65] [66] Enterovirus [67] [68] [69] Cytomegalovirus [22, 70–78] Viperin [79] self-antigens for which normally the immune system is tolerant but which upon modification have the potential to excerpt autoreactive immune responses. Modified lipoprotein particles have the capacity to interact with the endothelium, triggering their accumulation and retention in the subendothelial space. "
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    ABSTRACT: Atherosclerosis is a chronic inflammatory disorder characterised by the accumulation of monocytes/macrophages, smooth muscle cells, and lymphocytes within the arterial wall in response to the release of proinflammatory molecules. Such accumulation results in the formation of the atherosclerotic plaque, which would eventually evolve to complications such as total artery occlusion, rupture, calcification, or aneurysm. Although the molecular mechanism responsible for the development of atherosclerosis is not completely understood, it is clear that the immune system plays a key role in the development of the atherosclerotic plaque and in its complications. There are multiple antigenic stimuli that have been associated with the pathogenesis of atherosclerosis. Most of these stimuli come from modified self-molecules such as oxidised low-density lipoproteins (oxLDLs), beta2glycoprotein1 (beta2GP1), lipoprotein a (LP(a)), heat shock proteins (HSPs), and protein components of the extracellular matrix such as collagen and fibrinogen in the form of advanced glycation-end (AGE) products. In addition, several foreign antigens including bacteria such as Porphyromonas gingivalis and Chlamydia pneumoniae and viruses such as enterovirus and cytomegalovirus have been associated with atherosclerosis as potentially causative or bystander participants, adding another level of complexity to the analysis of the pathophysiology of atherosclerosis. The present review summarises the most important scientific findings published within the last two decades on the importance of antigens, antigen stimulation, and adaptive immune responses in the development of atherosclerotic plaques.
    Full-text · Article · Feb 2008 · Clinical and Developmental Immunology
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    • "At first glance, our infection data appear to controvert findings of significant neuronal degeneration and cell death. However, because infection with C. pneumoniae can both inhibit apoptosis and promote cell death by necrosis [28], and because we have continually observed C. pneumoniae infection in sporadic, late-onset AD brain tissues [17-19], the possibility that infection of neuronal cells in AD could lead to cell death by necrosis is compelling as this would implicate the inflammatory process. There are numerous reports of significant neuroinflammation in AD in which cell damage and death are thought to occur as the result of inflammation [34]. "
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    ABSTRACT: Chlamydophila (Chlamydia) pneumoniae is an intracellular bacterium that has been identified within cells in areas of neuropathology found in Alzheimer disease (AD), including endothelia, glia, and neurons. Depending on the cell type of the host, infection by C. pneumoniae has been shown to influence apoptotic pathways in both pro- and anti-apoptotic fashions. We have hypothesized that persistent chlamydial infection of neurons may be an important mediator of the characteristic neuropathology observed in AD brains. Chronic and/or persistent infection of neuronal cells with C. pneumoniae in the AD brain may affect apoptosis in cells containing chlamydial inclusions. SK-N-MC neuroblastoma cells were infected with the respiratory strain of C. pneumoniae, AR39 at an MOI of 1. Following infection, the cells were either untreated or treated with staurosporine and then examined for apoptosis by labeling for nuclear fragmentation, caspase activity, and membrane inversion as indicated by annexin V staining. C. pneumoniae infection was maintained through 10 days post-infection. At 3 and 10 days post-infection, the infected cell cultures appeared to inhibit or were resistant to the apoptotic process when induced by staurosporine. This inhibition was demonstrated quantitatively by nuclear profile counts and caspase 3/7 activity measurements. These data suggest that C. pneumoniae can sustain a chronic infection in neuronal cells by interfering with apoptosis, which may contribute to chronic inflammation in the AD brain.
    Full-text · Article · Feb 2008 · BMC Neuroscience
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    • "In human endothelial cells, oxLDL can cause inflammatory effects in the vascular wall, ultimately leading to cell death (Nazzal et al., 2006). Thus, the overproduction of oxLDL can induce cell insults and tissue dysfunction. "
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    ABSTRACT: Cerebral endothelial cells (CECs) are crucial components of the blood-brain barrier. Oxidized low-density lipoprotein (oxLDL) can induce cell injuries. In this study, we attempted to evaluate the effects of oxLDL on mouse CECs and its possible mechanisms. Mouse CECs were isolated from brain tissues and identified by immunocytochemical staining of vimentin and Factor VIII. oxLDL was prepared from LDL oxidation by copper sulfate. Exposure of mouse CECs to oxLDL decreased cell viability in concentration- and time-dependent manners. oxLDL time-dependently caused shrinkage of cell morphologies. Administration of oxLDL to CECs induced DNA fragmentation in concentration- and time-dependent manners. Analysis of the cell cycle revealed that oxLDL concentration- and time-dependently increased the proportion of CECs which underwent apoptosis. Analysis of confocal microscopy and immunoblot revealed that oxLDL significantly increased cellular and mitochondrial Bax levels as well as the translocation of this proapoptotic protein from the cytoplasm to mitochondria. In parallel with the increase in the levels and translocation of Bax, oxLDL time-dependently decreased the mitochondrial membrane potential. Exposure of mouse CECs to oxLDL decreased the amounts of mitochondrial cytochrome c, but enhanced cytosolic cytochrome c levels. The amounts of intracellular reactive oxygen species were significantly augmented after oxLDL administration. Sequentially, oxLDL increased activities of caspase-9, -3, and -6 in time-dependent manners. Pretreatment with Z-VEID-FMK, an inhibitor of caspase-6, significantly decreased caspase-6 activity and the oxLDL-induced DNA fragmentation and cell apoptosis. This study showed that oxLDL induces apoptotic insults to CECs via signal-transducing events, including enhancing Bax translocation, mitochondrial dysfunction, cytochrome c release, increases in intracellular reactive oxygen species, and cascade activation of caspase-9, -3, and -6. Therefore, oxLDL can damage the blood-brain barrier through induction of CEC apoptosis via a Bax-mitochondria-caspase protease pathway.
    Full-text · Article · Mar 2007 · Toxicology and Applied Pharmacology
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