It is now widely accepted that the development of atherosclerotic lesions involves a chronic inflammatory response that includes both innate and adaptive immune mechanisms. However, it is still unclear precisely what induces the inflammatory response. Furthermore, inflammation within the blood vessel can be divided into direct mechanisms where the primary inflammatory events occur within the intima of the blood vessel and contribute to both the initiation and progression of the plaques and indirect mechanisms where inflammation at non-vascular sites can contribute to the progression of the lesions. The direct mechanisms include lipid deposition and modification, influx of lipoprotein associated factors and microparticles derived from many different cell types, and possibly bacterial and viral infection of vascular cells. Indirect mechanisms derive from inflammation related to autoimmune diseases, smoking, respiratory infection, and pollution exposure, and possibly periodontal disease and gastric infection. The mechanisms include secretion of cytokines and other inflammatory factors into the circulation with subsequent uptake into the plaques, egress and recruitment of activated inflammatory cells, formation of dysfunctional HDL and cross reactive autoantibodies.
The goal of this study was to determine whether the A1 adenosine receptor (AR) plays a role in atherosclerosis development and to explore its potential mechanisms.
Methods and results
Double knockout (DKO) mice, deficient in the genes encoding A1 AR and apolipoprotein E (apoE), demonstrated reduced atherosclerotic lesions in aortic arch (en face), aortic root, and innominate arteries when compared with apoE-deficient mice (APOE-KO) of the same age. Treating APOE-KO with an A1 AR antagonist (DPCPX) also led to a concentration-dependent reduction in lesions. The total plasma cholesterol and triglyceride levels were not different between DKO and APOE-KO; however, higher triglyceride was observed in DKO fed a high-fat diet. DKO also had higher body weights than APOE-KO. Plasma cytokine concentrations (IL-5, IL-6, and IL-13) were significantly lower in DKO. Proliferating cell nuclear antigen expression was also significantly reduced in the aorta from DKO. Despite smaller lesions in DKO, the composition of the innominate artery lesion and cholesterol loading and efflux from bone marrow-derived macrophages of DKO were not different from APOE-KO.
The A1 AR may play a role in the development of atherosclerosis, possibly due to its pro-inflammatory and mitogenic properties.
A1 adenosine receptor; Apolipoprotein E; Cytokines; 1,3-Dipropyl-8-cyclopentylxanthine (DPCPX); IL-13
Vascular calcification is highly correlated with cardiovascular disease morbidity and mortality. Osteoprotegerin (OPG) is a secreted decoy receptor for Receptor Activator of NF-kappaB Ligand (RANKL). Inactivation of OPG in apolipoprotein E deficient mice (ApoE−/−) increases lesion size and calcification. The mechanism(s) by which OPG is athero-protective and anti-calcific have not been entirely determined. We investigated whether OPG deficient vascular smooth muscle cells (VSMCs) are more susceptible to mineralization and whether RANKL mediates this process.
Lesion free aortas from 12 week old ApoE−/−OPG−/− mice had spotty calcification, an appearance of osteochondrogenic factors, and a decrease of smooth muscle markers when compared to ApoE−/−OPG+/+ aortas. In osteogenic conditions, VSMCs isolated from ApoE−/−OPG−/− (KO-VSMC) mice deposited more calcium than VSMCs isolated from ApoE−/−OPG+/+ (WT-VSMC) mice. Gene expression and biochemical analysis indicated accelerated osteochondrogenic differentiation. Ablation of RANKL signaling in KO-VSMCs rescued the accelerated calcification. While WT-VSMCs did not respond to RANKL treatment, KO-VSMCs responded with enhanced calcification and the upregulation of osteochondrogenic genes. RANKL strongly induced IL-6, which partially mediated RANKL-dependent calcification and gene expression in KO-VSMCs.
OPG inhibits vascular calcification by regulating the pro-calcific effects of RANKL on VSMCs and is thus a possible target for therapeutic intervention.
OPG; RANKL; IL-6; smooth muscle cells; vascular calcification; osteochondrogenic differentiation
Several lines of evidence have associated Chlamydia
pneumoniae with cardiovascular disease including acceleration of
atherosclerotic lesion progression in hyperlipidemic animal models by infection.
Many of the proatherogenic effects of oxidized low density lipoprotein (ox-LDL)
occur through the activation of the lectin-like ox-LDL receptor (LOX-1).
C. pneumoniae upregulates expression of the LOX-1mRNA,
promotes uptake of ox-LDL, and utilizes the LOX-1 receptor for infectivity. The
overall goal of this study was to determine if C. pneumoniae
organisms upregulated LOX-1 protein expression in vascular cells and whether
up-regulation of pro-atherogenic factors by C. pneumoniae
occurred through LOX-1. C. pneumoniae induced LOX-1 protein
expression in both endothelial cells and RAW macrophages. Upregulation was
prevented by preincubation of cells with LOX-1 antibody prior to infection.
Similarly, C. pneumoniae upregulated protein expression of
adhesion molecules, MMP-1, and MMP-3, which was mitigated by anti-LOX-1
antibody. Prior treatment of organisms with PNGase, which removes the chlamydial
glycan that is N-linked to the major outer membrane, abolished C.
pneumoniae up-regulation of LOX-1. These studies suggest that
activation of LOX-1 expression occurs through binding of the chlamydial glycan
and provide one mechanism by which C. pneumoniae infection
could play a role in the pathogenesis of atherosclerosis.
Chlamydia; LOX-1 receptor; atherosclerosis; adhesion molecules; glycan
Glutamate-cysteine ligase (GCL) is the rate-limiting step in glutathione synthesis. The enzyme is a hetero-dimer composed of a catalytic subunit GCLC and a modifier subunit GCLM.
We generated apo E−/− mice deficient in GCLM (apoE−/−/Gclm−/−) and transgenic mice that over-express GCLC specifically in macrophages (apoE−/−/Gclc-Tg) to test the hypothesis that significantly altering the availability of glutathione has a measurable impact on both the initiation and progression of atherosclerosis.
Methods and Results
Atherosclerotic plaque size and composition were measured in the innominate artery in chow-fed male and female mice at 20, 30, 40 and 50 weeks of age and in the aortic sinus at 40 or 50 weeks of age. The apoE−/−/Gclm−/− mice more rapidly developed complex lesions while the apoE−/−/Gclc-Tg mice had reduced lesion development as compared to the littermate apo E−/− control mice. Transplant of bone marrow from the apoE−/−/Gclm−/− and apoE−/−/Gclc-Tg mice into apo E−/− mice with established lesions also stimulated or inhibited further lesion development at 30 weeks post-transplant.
Gain and loss of function in the capacity to synthesize glutathione especially in macrophages has reciprocal effects on the initiation and progression of atherosclerosis at multiple sites in apo E−/− mice.
Atherosclerosis; macrophages; glutathione; apo E−/−
Vascular calcification is highly correlated with cardiovascular disease (CVD) morbidity and mortality, and it is associated with inflammation. Receptor Activator of NF-κB Ligand (RANKL) inhibition in vivo has been shown to reduce vascular calcification in mouse atherosclerosis. With this study we tested the hypothesis that RANKL regulates smooth muscle cell calcification by modulating macrophage production of pro-calcific cytokines.
We used a bone marrow-derived macrophage (BMDM)/smooth muscle cell (SMC) co-culture system and examined the effects of RANKL on BMDM activation and SMC matrix calcification.
Treatment with RANKL alone did not stimulate SMC calcification induced by elevated phosphate. BMDMs differentiated with macrophage colony-stimulating factor (M-CSF) and placed in co-culture with SMCs, increased phosphate-induced SMC calcification. RANKL added to the BMDM/SMC co-cultures further enhanced SMC calcification. Treatment of BMDMs with RANKL resulted in increased expression of IL-6 and TNF-α. Thus, increased expression of these pro-calcific cytokines in macrophages may mediate RANKL-induced SMC calcification in a paracrine fashion. Addition of neutralizing IL-6 and TNF-α antibodies together with RANKL treatment significantly reduced the RANKL induction of SMC calcification.
RANKL activation of pro-inflammatory and pro-calcific pathways in macrophages may contribute to vascular calcification and inflammation.
RANKL; macrophages; vascular calcification; TNF-α; IL-6
The acute phase response to C. pneumoniae infection was analyzed over a 72 hr period post-infection in C57BL/6J mice. A single intranasal inoculation stimulated statistically significant increases in the plasma levels of IL-2, IL-5, IL-6, IL-10, IL-12, GM-CSF, IFN-γ, and serum amyloid A but not TNF-α, IL-1β, IL-4 and serum amyloid P. There was also a decrease in the activity of the HDL protective enzyme paraoxonase as well as a reduced ability of HDL to prevent oxidation of palmitoyl-2-arachidonyl-sn-glycerol-3-phosphocholine by hydroperoxyoctadecadienoic acid at 48 and 72 hrs post-infection. To determine whether the C. pneumoniae induced acute phase response had any effect on atherosclerotic plaque stability, we measured the frequency of intra-plaque hemorrhage as a marker of plaque disruption in the innominate arteries of apolipoprotein E deficient mice at 29–30 weeks and 1.5–2.0 years of age. There was an increased frequency of intra-plaque hemorrhage only in the older mice infected with the live organism (8/14) as compared to mice treated with killed C. pneumoniae (2/11) or sham inoculated with PBS (2/12). These results suggest that acute phase reactant proteins produced in response to pulmonary infection with C. pneumoniae may contribute to the progression and destabilization of atherosclerotic lesions.
Chlamydia pneumoniae; Inflammation; Cytokines; Mice
Chlamydia pneumoniae; atherosclerosis; persistence; antibiotics; clinical trials
Antioxidants and soy isoflavones inhibit the development of fatty streaks in various animal models. However, clinical trials in humans have not entirely supported a cardio-protective role for antioxidants or isoflavones. Thus, we examined the effects of antioxidants and genistein on the progression and composition of established, advanced atherosclerotic lesions in the innominate arteries (IA) of older apolipoprotein E-deficient (apoE-/-) mice. Thirty week old male apoE-/- mice were fed chow with or without genistein (0.27% w/w) for 6, 12 and 24 weeks. Twenty week old male apoE-/- mice were fed chow with or without a cocktail of antioxidants (vitamin E 0.2% w/w, vitamin C 0.05% w/w, and beta carotene 0.5% w/w) for 10, 16, and 22 weeks. There were no significant differences in total plasma cholesterol, body weight, average area of the lesion or media, or changes in lesion composition with either treatment in comparison to chow-fed control mice. This data may help explain why there have not been consistent protective effects of antioxidants and isoflavones on cardiovascular disease in human clinical trials.
Antioxidants; Soy Isoflavones; Genistein; Atherosclerosis; Apolipoprotein E deficient mice
Strong associations have been observed between exposure to fine ambient particulate matter (PM2.5) and adverse cardiovascular outcomes. In particular, exposure to traffic related PM2.5 has been associated with increases in left ventricular hypertrophy, a strong risk factor for cardiovascular mortality. As much of traffic related PM2.5 is derived from diesel exhaust (DE), we investigated the effects of chronic DE exposure on cardiac hypertrophy and heart failure in the adult mouse by exposing mice to DE combined with either of two mouse models of cardiac hypertrophy: angiotensin II infusion or pressure overload induced by transverse aortic banding.
Wild type male C57BL/6 J mice were either infused with angiotensin II (800 ng/kg/min) via osmotic minipump implanted subcutaneously for 1 month, or underwent transverse aortic banding (27 gauge needle 1 week for observing acute reactions, 26 gauge needle 3 months or 6 months for observing chronic reactions). Vehicle (saline) infusion or sham surgery was used as a control. Shortly after surgery, mice were transferred to our exposure facility and randomly assigned to either diesel exhaust (300 or 400 μg/m3) or filtered air exposures. After reaching the end of designated time points, echocardiography was performed to measure heart structure and function. Gravimetric analysis was used to measure the ventricular weight to body weight ratio. We also measured heart rate by telemetry using implanted ambulatory ECG monitors.
Both angiotensin II and transverse aortic banding promoted cardiac hypertrophy compared to vehicle or sham controls. Transverse aortic banding for six months also promoted heart failure in addition to cardiac hypertrophy. In all cases, DE failed to exacerbate the development of hypertrophy or heart failure when compared to filtered air controls. Prolonged DE exposure also led to a decrease in average heart rate.
Up to 6-months of DE exposure had no effect on cardiac hypertrophy and heart function induced by angiotensin II stimulation or pressure overload in adult C57BL/6 J mice. This study highlights the potential importance of particle constituents of ambient PM2.5 to elicit cardiotoxic effects. Further investigations on particle constituents and cardiotoxicity are warranted.
Diesel exhaust; PM2.5; Air pollution; Cardiac hypertrophy; Heart failure
Hyperhomocysteinemia is an independent risk factor for atherosclerosis. Uptake of homocysteine induces oxidative stress in macrophages. Antioxidant response elements (AREs) are regulatory elements within promoters of genes, which protect cells against oxidative stress. The current study investigated whether homocysteine induces transcription of glutamate-cysteine ligase (Gcl), via ARE driven gene expression in mouse macrophages. Gcl is the rate-limiting enzyme in the synthesis of glutathione, an important endogenous antioxidant. Gcl is heterodimeric and the genes encoding the subunits of Gcl contain several AREs within their 5′-promoter regions. Treatment of mouse macrophages with d-/l-homocysteine (50 µM) induced depletion of intracellular glutathione and a compensatory increase in Gcl activity. Electro mobiliy shift assays demonstrated increased binding of nuclear proteins to ARE-containing oligonucleotides. Real-time RT-PCR revealed increased mRNA-expression of the catalytic subunit of Gcl (Gclc) after treatment with homocysteine, and this occurred via increased transcription as demonstrated with luciferase promoter reporter constructs for Gclc. Additional site directed mutagenesis demonstrated that ARE4 plays a direct role in mediating induction of Gclc by homocysteine. Supershift analysis and Western blotting revealed that Nrf2 signalling is critical in homocysteine-induced activation of ARE4. Inhibition of MAP kinase activity reduced binding of nuclear proteins to the AREs, nuclear expression of Nrf2 and mRNA expression of Gclc. Western blotting demonstrated phosporylation of ERK1/2 in homocysteine treated macrophages. These data suggest that ARE-driven gene expression of Gclc via a MEK/Nrf2 pathway could help to protect macrophages from oxidative stress due to hyperhomocysteinemia.
Homocysteine; Atherosclerosis; Oxidative stress; Glutamate-cysteine ligase; Antioxidant response element
The association of Chlamydia pneumoniae and atherosclerosis has been well documented. Recently, it has been demonstrated that C. pneumoniae upregulates expression of the lectin-like ox-LDL receptor (LOX-1) in endothelial cells. Many of the pro-atherogenic effects of ox-LDL occur through its activation of and uptake by LOX-1. This class E scavenger receptor contains a carbohydrate recognition domain common to the C type lectin family. Previously, we have demonstrated that the major outer membrane protein of the chlamydiae is glycosylated and glycan removal abrogates infectivity of C. pneumoniae for endothelial cells. In this study, we investigated whether C. pneumoniae binds to LOX-1. The results show that 1) infection of endothelial cells by C. pneumoniae is inhibited by ligands that bind to the LOX-1 receptor, but not by ligands binding to other scavenger receptors; 2) anti-LOX-1 antibody inhibits C. pneumoniae infectivity, while antibodies against other scavenger receptors do not; 3) anti-LOX-1 antibody inhibits attachment of C. pneumoniae to endothelial cells; and 4) C. pneumoniae co-localizes with LOX-1. These effects were not observed for Chlamydia trachomatis. In conclusion, C. pneumoniae binds to the LOX-1 receptor, which is known to promote atherosclerosis.
Chlamydia pneumoniae; LOX-1 receptor; Atherosclerosis
Magnetic nanoparticles are promising molecular imaging agents due to their relative high relaxivity and the potential to modify surface functionality to tailor biodistribution. In this work we describe the synthesis of magnetic nanoparticles using organic solvents with organometallic precursors. This method results in nanoparticles that are highly crystalline, and have uniform size and shape. The ability to create a monodispersion of particles of the same size and shape results in unique magnetic properties that can be useful for biomedical applications with MR imaging. Before these nanoparticles can be used in biological applications, however, means are needed to make the nanoparticles soluble in aqueous solutions and the toxicity of these nanoparticles needs to be studied.
We have developed two methods to surface modify and transfer these nanoparticles to the aqueous phase using the biocompatible co-polymer, Pluronic F127. Cytotoxicity was found to be dependent on the coating procedure used. Nanoparticle effects on a cell-culture model was quantified using concurrent assaying; a LDH assay to determine cytotoxicity and an MTS assay to determine viability for a 24 hour incubation period. Concurrent assaying was done to insure that nanoparticles did not interfere with the colorimetric assay results.
This report demonstrates that a monodispersion of nanoparticles of uniform size and shape can be manufactured. Initial cytotoxicity testing of new molecular imaging agents need to be carefully constructed to avoid interference and erroneous results.
MRI; molecular imaging; nanoparticles; superparamagnetic agents; cytotoxicity; Colorimetric Assay; Pluronics
The bone morphogenetic proteins (BMP), a family of morphogens, have been implicated as mediators of calcification and inflammation in the vascular wall.
To investigate the effect of altered expression of Matrix Gla Protein (MGP), an inhibitor of BMP, on vascular disease.
Methods and Results
We used MGP transgenic or MGP deficient mice bred to apolipoprotein E mice, a model of atherosclerosis. MGP overexpression reduced vascular BMP activity, atherosclerotic lesion size, intimal and medial calcification, and inflammation. It also reduced expression of the activin-like kinase receptor (ALK)1 and the vascular endothelial growth factor (VEGF), part of a BMP-activated pathway that regulates angiogenesis and may enhance lesion formation and calcification. Conversely, MGP deficiency increased BMP activity, which may explain the diffuse calcification of vascular medial cells in MGP deficient aortas, and the increase in expression of ALK1 and VEGF. Unexpectedly, atherosclerotic lesion formation was decreased in MGP deficient mice, which may be explained by a dramatic reduction in expression of endothelial adhesion molecules limiting monocyte infiltration of the artery wall.
Our results indicate that BMP signaling is a key regulator of vascular disease, requiring careful control to maintain normal vascular homeostasis.
Bone morphogenetic protein; Matrix Gla protein; Atherosclerosis; Vascular calcification; Inflammation
The innominate artery is a predilection site for atherosclerotic lesion formation in hyperlipidemic mice. The lesions at this site in chow-fed apo E−/− mice progress from fatty streaks through stages that include atheroma with large necrotic areas, fibro-fatty nodules containing chondrocyte-like cells and highly calcified, acellular plaques. The advanced lesions in the innominate arteries of the apo E−/− mice exhibit a reproducible frequency of intra-plaque hemorrhage that occurs primarily as a result of fissures through lateral fatty streaks that form adjacent to or on top of the established plaques. However, this plaque disruption is not equivalent to plaque rupture in human lesions where there is rupture of well formed fibrous caps. The plaque disruption in the lesions of the chow-fed apo E−/− mice also do not lead to formation of occlusive thrombi, the predominant marker of plaque rupture in humans. Thus, although the lesions in the innominate arteries of hyperlipidemic mice progress to very advanced stages of the disease, they are not, in our opinion a model in which to study the mechanisms of plaque rupture in humans. The advanced lesions in the innominate arteries of the apo E−/− mice may however be adequate models for studying vascular fibrosis and calcification.
Chlamydia pneumoniae, a common respiratory pathogen, has been associated with cardiovascular disease. C. pneumoniae infection accelerates atherosclerotic lesion development in hyperlipidemic animals. Retinoic acid, an anti-oxidant, inhibits infection of endothelial cells by C. pneumoniae. The present study demonstrated that retinoic acid suppresses the acceleration of foam cell lesion development induced by C. pneumoniae in hyperlipidemic C57BL/6J mice. Retinoic acid treatment had no effect on foam cell lesion development in uninfected animals. Lung infection and duration was decreased in treated mice, suggesting one mechanism by which retinoic acid reduces C. pneumoniae accelerated foam cell lesion formation in hyperlipidemic mice.
Chlamydia pneumoniae; Atherosclerosis; Mouse model Retinoic acid treatment
Interactions between monocytes/macrophages and endothelial cells play an important role in the pathogenesis of atherosclerosis, and the adherence of monocytes to the arterial endothelium is one of the early events in atherogenesis. In the present study, peritoneal macrophages harvested from green fluorescent protein (GFP) transgenic mice were used to analyze how Chlamydia pneumoniae infection affects the adherence of GFP-macrophages to mouse endothelial cells in vitro and to the aorta from normolipidemic and hyperlipidemic mice ex vivo. In vitro studies showed that C. pneumoniae-infected GFP-macrophages adhered better than uninfected macrophages to endothelial cells and GFP-macrophages adhered better to infected than uninfected endothelial cells. The ex vivo studies showed that C. pneumoniae-infected macrophages adhered better than uninfected macrophages to aortas from both normolipidemic and hyperlipidemic C57BL/6J mice and apolipoprotein E (ApoE)-deficient mice. In contrast, adherence of C. pneumoniae-infected macrophages to the aortas of intercellular adhesion molecule 1 (ICAM-1) knockout mice was not enhanced, suggesting that ICAM-1 is crucial for activation of the adherence of C. pneumoniae-infected macrophages to the endothelium. In conclusion, the present study defined a homing mechanism by which C. pneumoniae promotes the adherence of mononuclear phagocytes to the endothelium at the site of atherosclerotic lesion formation to promote the progression of atherosclerosis.
Chlamydiae are obligate intracellular gram-negative bacteria and are dependent on the host cell for ATP. Thus, chlamydial infection may alter the intracellular levels of ATP and affect all energy-dependent processes within the cell. We have shown that both live C. pneumoniae and inactivated C. pneumoniae induce markers of cell death prior to completion of the bacterial growth cycle. As depletion of ATP could account for the observed increase in cell death, the effects of C. pneumoniae on ATP concentrations within mouse macrophages were investigated. Live, heat-killed, and UV-inactivated C. pneumoniae cultures (at multiplicities of infection [MOIs] of 0.01, 0.1, and 1.0) were incubated with mouse bone marrow macrophages isolated from C57BL/6J mice and mice deficient in Toll-like receptors. Treatment of the macrophages with both live and inactivated C. pneumoniae increased the ATP content of the cells. In cells infected with live C. pneumoniae, the increase was inversely proportional to the MOI. In cells treated with inactivated C. pneumoniae, the increase in ATP content was smaller than that induced by infection with live organisms and was proportional to the MOI. The increase in ATP content early in the developmental cycle was independent of the growth of C. pneumoniae, while sustained induction required live organisms. The capacity of C. pneumoniae to increase the ATP content was ablated in macrophages deficient in expression of either Toll-like receptor 2 or the Toll-like receptor accessory protein MyD88. In contrast, no effect was observed in macrophages lacking expression of Toll-like receptor 4.
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.
The role of tumor necrosis factor alpha (TNF-α) in Chlamydia pneumoniae atherogenesis was evaluated in TNF-α p55 receptor-deficient C57BL/6J mice fed a high-fat/high-cholesterol diet. No acceleration of atherosclerotic lesion development was observed in infected mice compared to uninfected mice, indicating that TNF-α plays a role in the acceleration of atherosclerosis by C. pneumoniae.
Chlamydia pneumoniae has been shown to accelerate atherosclerotic lesion development in hyperlipidemic animals. This study showed that C. pneumoniae did not accelerate lesion development in mice if a high-fat/high-cholesterol diet was started after infection, indicating that C. pneumoniae is a co-risk factor with hyperlipidemia for cardiovascular disease.
We have previously demonstrated that Chlamydia pneumoniae accelerates plaque formation in apolipoprotein E-deficient (ApoE−/−) mice following intranasal inoculations. In this study, we evaluated the effect of respiratory tract infection with Chlamydia trachomatis on the progression of atherosclerosis in ApoE−/− mice. The study showed that in contrast to infection with Chlamydia pneumoniae, infection of the lung and aorta with C. trachomatis was mild and transient and did not significantly accelerate plaque development.
Chlamydia pneumoniae infection induces inflammatory changes in blood vessels in normocholesterolemic rabbits, but it is not known whether the same phenomenon occurs in other animal models. Thus, in this study, C57BL/6J mice were inoculated with C. pneumoniae. Inflammatory changes in the heart or aorta were observed in a small number of chronically infected mice. No evidence of atherosclerotic lesions was found in any of the mice. These findings suggest that chronic C. pneumoniae infection can induce inflammatory changes in the heart and aorta of C57BL/6J mice, but does not initiate definitive atherosclerosis.