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

ArticleinThe Journal of Infectious Diseases 193(1):136-45 · February 2006with8 Reads
DOI: 10.1086/498617 · Source: PubMed
Abstract
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.
    • "However, no data regarding the effects induced by Pg in the context of Ox-LDL or TNF-α pre-treated ECs were available. A cumulative effect between Ox-LDL and Pg infection on cell viability has been observed as demonstrated for C.pneumoniae [27,39]. Pg-LPS is one of the major virulence factors of Pg and endotoxemia has been considered to induce systemic inflammation contributing to atherosclerosis worsening [14,39] . "
    [Show abstract] [Hide abstract] ABSTRACT: Objective Clinical studies demonstrated a potential link between atherosclerosis and periodontitis. Porphyromonas gingivalis (Pg), one of the main periodontal pathogen, has been associated to atheromatous plaque worsening. However, synergism between infection and other endothelial stressors such as oxidized-LDL or TNF-α especially on endothelial cell (EC) death has not been investigated. This study aims to assess the role of Pg on EC death in an inflammatory context and to determine potential molecular pathways involved. Methods Human umbilical vein ECs (HUVECs) were infected with Pg (MOI 100) or stimulated by its lipopolysaccharide (Pg-LPS) (1μg/ml) for 24 to 48 hours. Cell viability was measured with AlamarBlue test, type of cell death induced was assessed using Annexin V/propidium iodide staining. mRNA expression regarding caspase-1, -3, -9, Bcl-2, Bax-1 and Apaf-1 has been evaluated with RT-qPCR. Caspases enzymatic activity and concentration of APAF-1 protein were evaluated to confirm mRNA results. Results Pg infection and Pg-LPS stimulation induced EC death. A cumulative effect has been observed in Ox-LDL pre-treated ECs infected or stimulated. This effect was not observed in TNF-α pre-treated cells. Pg infection promotes EC necrosis, however, in infected Ox-LDL pre-treated ECs, apoptosis was promoted. This effect was not observed in TNF-α pre-treated cells highlighting specificity of molecular pathways activated. Regarding mRNA expression, Pg increased expression of pro-apoptotic genes including caspases-1,-3,-9, Bax-1 and decreased expression of anti-apoptotic Bcl-2. In Ox-LDL pre-treated ECs, Pg increased significantly the expression of Apaf-1. These results were confirmed at the protein level. Conclusion This study contributes to demonstrate that Pg and its Pg-LPS could exacerbate Ox-LDL and TNF-α induced endothelial injury through increase of EC death. Interestingly, molecular pathways are differentially modulated by the infection in function of the pre-stimulation.
    Full-text · Article · Apr 2016
    • "The increased production of ROS, induced by C. pneumoniae, has also been demonstrated in platelets, endothelial cells and vascular smooth muscle cells (VSMCs) causing both LDL oxidation and further pro-atherogenic effects, such as endothelial dysfunction, VSMC proliferation and migration, and platelet adhesion and aggregation [34]. In addition, there is also the evidence that C. pneumoniae and oxidized LDL (oxLDL) induce necrosis in macrophages as well as in endothelial cells, thus contributing to vascular inflammation and progression of atherosclerotic lesion [35,36]. The growing body of evidence linking C. pneumoniae to atherosclerosis through the elicitation of oxidative stress in the vascular wall raises interesting questions concerning the possibilities of CVD prevention by limiting ROS production and/or accelerating their inactivation. "
    [Show abstract] [Hide abstract] ABSTRACT: Chlamydia pneumoniae, a pathogenic bacteria responsible for respiratory tract infections, is known as the most implicated infectious agent in atherosclerotic cardiovascular diseases (CVDs). Accumulating evidence suggests that C. pneumoniae-induced oxidative stress may play a critical role in the pathogenesis of CVDs. Indeed, the overproduction of reactive oxygen species (ROS) within macrophages, endothelial cells, platelets and vascular smooth muscle cells (VSMCs) after C. pneumoniae exposure, has been shown to cause low density lipoprotein oxidation, foam cell formation, endothelial dysfunction, platelet adhesion and aggregation, and VSMC proliferation and migration, all responsible for the typical pathological changes of atherosclerotic plaque. The aim of this review is to improve our insight into C. pneumoniae-induced oxidative stress in order to suggest potential strategies for CVD prevention. Several antioxidants, acting on multi-enzymatic targets related to ROS production induced by C. pneumoniae, have been discussed. A future strategy for the prevention of C. pneumoniae-associated CVDs will be to target chlamydial HSP60, involved in oxidative stress.
    Full-text · Article · Dec 2014
    • "Thirdly, C. pneumoniae-mediated oxidative stress contributes to endothelial dysfunction through vascular inflammation. Specifically, C. pneumoniae has been shown to promote endothelial cell necrosis and, as a result, to enhance the inflammatory effect of oxLDL [95]. A recent study has also shown that oxLDL-induced inflammation may be related to elevated levels of LOX-1, mediated by the phosphoinositide 3-kinase-Akt signaling pathway, endothelial NO synthase activation, NOX-mediated ROS production and mitogen activated protein kinase (MAPK) activation in GroEL1-stimulated human coronary artery endothelial cells [48]. "
    [Show abstract] [Hide abstract] ABSTRACT: Chlamydia pneumoniae, an obligate intracellular pathogen, is known as a leading cause of respiratory tract infections and, in the last two decades, has been widely associated with atherosclerosis by seroepidemiological studies, and direct detection of the microorganism within atheroma. C. pneumoniae is presumed to play a role in atherosclerosis for its ability to disseminate via peripheral blood mononuclear cells, to replicate and persist within vascular cells, and for its pro-inflammatory and angiogenic effects. Once inside the vascular tissue, C. pneumoniae infection has been shown to induce the production of reactive oxygen species in all the cells involved in atherosclerotic process such as macrophages, platelets, endothelial cells, and vascular smooth muscle cells, leading to oxidative stress. The aim of this review is to summarize the data linking C. pneumoniae-induced oxidative stress to atherosclerotic lesion development.
    Full-text · Article · Jul 2013
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