Biomedical subjects

M E Rosenfeld

Publications and source records attributed to M E Rosenfeld.

At least 19 recordsLinked to original sources

PubMed2005

A 6 week course of azithromycin treatment has no beneficial effect on atherosclerotic lesion development in apolipoprotein E-deficient mice chronically infected with Chlamydia pneumoniae.

OBJECTIVES: To evaluate whether antimicrobial chemotherapy prevents acceleration of atherosclerotic lesion development induced by infection with Chlamydia pneumoniae. METHODS: ApoE-deficient mice which develop hyperlipidaemia and atherosclerosis spontaneously were inoculated intranasally with C. pneumoniae. Animals were treated with azithromycin for 6 weeks after the third inoculation and the atherosclerotic lesion areas in the aortic sinus were measured by computer-assisted morphometry. RESULTS: At 12 weeks post-infection, infected untreated animals developed significantly larger lesion areas compared with sham-inoculated controls (8.7 x 10(4)+/-2.3 x 10(4) microm(2) versus 5.6 x 10(4)+/-2.4 x 10(4) microm(2)). However, there were no differences in lesion size of infected mice treated with azithromycin in comparison with untreated infected controls (11.0 x 10(4)+/-3.0 x 10(4) microm(2) versus 8.7 x 10(4)+/-2.3 x 10(4) microm(2)). CONCLUSIONS: Antibiotic treatment against C. pneumoniae has no beneficial effects on hyperlipidaemia-induced atherosclerosis accelerated by C. pneumoniae in a mouse model.

Animals↗

PubMed2004

Development of a lipoprotein based molecular imaging MR contrast agent for the noninvasive detection of early atherosclerotic disease.

INTRODUCTION: Currently there are no clinically available means of noninvasively detecting early atherosclerotic disease because these lesions are characterized by an accumulation of extracellular lipid and foam cells, but a lack of significant wall thickening or architectural distortion. OBJECTIVE: We hypothesize that a paramagnetically labeled low density lipoprotein (LDL) could serve as a functional probe to detect sites of abnormal lipid metabolism in the vessel wall that represent sites of early disease. METHODS: Isolated LDL was first incubated with manganese-mesoporphyrin, a hydrophobic MR contrast agent (MnMeso). Size exclusion chromatography and absorption mass spectroscopy were performed on the resulting samples to prove that an association between the two occurred. Subsequently, foam cell cultures (n=7) were incubated (10-30 microg/ml for 48 h) with these labeled lipoproteins and the T1 relaxivity of centrifuged pellets of these cells was determined by using an inversion recovery sequence on a 1.5T scanner. These results were compared to control measurements made from foam cell cultures fed unlabeled lipoproteins (n=7). RESULTS: Measured T1 relaxation times of the cells fed the MnMeso-LDL (443.3 +/- 51.8 ms) was significantly different from the T1 relaxivity obtained from cells fed unlabeled lipoproteins (661.3 +/- 60.9 ms). These findings indicate that the amount of contrast bound to the constructed lipoproteins is sufficient to produce measurable MR signal changes noninvasively. CONCLUSIONS: The study results support the feasibility of future in vivo MR experiments with labeled lipoproteins to assess lipoprotein kinetics in the vessel wall, which will hopefully provide a means of detecting early atherosclerotic disease.

Animals↗

PubMed2001

Human monocyte-derived insulin-like growth factor-2 enhances the infection of human arterial endothelial cells by Chlamydia pneumoniae.

It has been shown that infection of human endothelial cells by Chlamydia pneumoniae is enhanced by co-culturing endothelial cells with human monocytes and is mediated by monocyte-derived soluble factors. This study was conducted to identify the infectivity-enhancing factor. Serum-free conditioned medium of human monocytic cells was fractionated by ultrafiltration. The enhancing activity was found in the fraction in the molecular mass range between 5000 and 10,000 kDa. Recombinant human insulin-like growth factor (IGF)-1 or -2, with a molecular mass of 7500 kDa, was added to the culture medium of human endothelial cells for growing C. pneumoniae. Only IGF-2 enhanced C. pneumoniae growth. Pretreatment of the conditioned medium with a monoclonal antibody against IGF-2 blocked the enhancing activity. This suggests that the infectivity-enhancing factor is IGF-2 and that paracrine interactions between monocytes and endothelial cells in vivo can induce secretory products and sustain infection with C. pneumoniae within atherosclerotic lesions.

Antibodies, Monoclonal↗

PubMed2001

Chlamydia pneumoniae infection accelerates hyperlipidemia induced atherosclerotic lesion development in C57BL/6J mice.

Considerable evidence of an association between Chlamydia pneumoniae infections and cardiovascular disease has emerged. Animal models using genetically altered mice and hypercholesterolemic rabbits have shown a pathogenic role of C. pneumoniae in accelerating atherosclerotic plaque development. In the present study, we evaluated the effect of chronic C. pneumoniae infection on atherosclerosis in C57BL/6J mice, fed either a regular chow diet or a high fat, high cholesterol diet. Infected animals on an atherogenic diet developed significantly larger lesion areas compared with control mice at 18 weeks (2.5-fold increase; 4177+/-777 vs. 1650+/-808 microm(2); P<0.05) and 24 weeks of age (3.3-fold increase; 14139+/-4147 vs. 4298+/-869 microm(2); P<0.02). This study shows that chronic C. pneumoniae infection accelerates atherosclerotic lesion development in diet induced hypercholesterolemic mice, indicating that C. pneumoniae is a co-risk factor of hyperlipidemia in atherogenesis.

Animals↗

PubMed2001

Expression of suppressors of cytokine signaling during liver regeneration.

The cytokines TNF and IL-6 play a critical role early in liver regeneration following partial hepatectomy (PH). Since IL-6 activates signal transducers and activators of transcription (STATs), we examined whether the suppressors of cytokine signaling (SOCS) may be involved in terminating IL-6 signaling. We show here that SOCS-3 mRNA is induced 40-fold 2 hours after surgery. SOCS-2 and CIS mRNA are only weakly induced, and SOCS-1 is not detectable. SOCS-3 induction after PH is transient and correlates with a decrease in STAT-3 DNA binding and a loss of tyrosine 705 phosphorylation. This response is markedly reduced in IL-6 knockout (KO) mice. TNF injection induces SOCS-3 mRNA in wild-type mice (albeit weakly compared with the increase observed after PH) but not in TNF receptor 1 or IL-6 KO mice. In contrast, IL-6 injection induces SOCS-3 in these animals, demonstrating a requirement for IL-6 in SOCS-3 induction. IL-6 injection into wild-type mice also induces SOCS-1, -2, and CIS mRNA, in addition to SOCS-3. Together, these results suggest that SOCS-3 may be a key component in downregulating STAT-3 signaling after PH and that SOCS-3 mRNA levels in the regenerating liver are regulated by IL-6.

Animals↗

PubMed2000

The good smooth muscle cells in atherosclerosis.

The formation of a fibrous cap made up of intimal smooth muscle cells and connective tissue is part of an attempt by the vessel wall to encapsulate the toxic products accumulating in the necrotic core of atherosclerotic lesions, and should be viewed as a beneficial healing response. In this review, we discuss the development of the intima and the potential origins of the intimal smooth muscle cell with a focus on the unique properties of these cells. We further discuss the role of intimal smooth muscle cells in plaque rupture and in wound healing, and the relationship of wound healing to the loss of lumen that occurs with development of advanced atherosclerotic lesions.

Animals↗

PubMed2000

Prevention of hepatic apoptosis and embryonic lethality in RelA/TNFR-1 double knockout mice.

Mice deficient in the nuclear factor kappaB (NF-kappaB)-transactivating gene RelA (p65) die at embryonic days 14-15 with massive liver apoptosis. In the adult liver, activation of the NF-kappaB heterodimer RelA/p50 can cause hepatocyte proliferation, apoptosis, or the induction of acute-phase response genes. We examined, during wild-type fetal liver development, the expression of the Rel family member proteins, as well as other proteins known to be important for NF-kappaB activation. We found these proteins and active NF-kappaB complexes in the developing liver from at least 2 days before the onset of lethality observed in RelA knockouts. This suggests that the timing of NF-kappaB activation is not related to the timing of lethality. We therefore hypothesized that, in the absence of RelA, embryos were sensitized to tumor necrosis factor (TNF) receptor 1 (TNFR-1)-mediated apoptosis. Thus, we generated mice that were deficient in both RelA and TNFR-1 to determine whether apoptotic signaling through TNFR-1 was responsible for the lethal phenotype. RelA/TNFR-1 double knockout mice survived embryonic development and were born with normal livers without evidence of increased hepatocyte apoptosis. These animals became runted shortly after birth and survived an average of 10 days, dying from acute hepatitis with an extensive hepatic infiltration of immature neutrophils. We conclude that neither RelA nor TNFR-1 is required for liver development and that RelA protects the embryonic liver from TNFR-1-mediated apoptotic signals. However, the absence of both TNFR-1 signaling and RelA activity in newborn mice makes these animals susceptible to endogenous hepatic infection.

Animals↗

PubMed2000

Low level expression of hormone-sensitive lipase in arterial macrophage-derived foam cells: potential explanation for low rates of cholesteryl ester hydrolysis.

Conversion of arterial macrophages into foam cells is a key process involved in both the initiation and progression of atherosclerotic lesions. Foam cell formation involves the progressive accumulation and storage of lipoprotein-derived cholesteryl esters. The resulting imbalance in cholesterol metabolism in arterial foam cells may be due in part to an inadequately low level of cytoplasmic neutral cholesteryl ester hydrolase (NCEH) activity. In this study, we have demonstrated that hormone-sensitive lipase (HSL) mRNA is expressed at very low levels in macrophage-derived foam cells, using the unique approach of extracting mRNA from macrophage-derived foam cells purified from human and rabbit atherosclerotic plaques coupled with reverse transcriptase polymerase chain reaction (RT-PCR). We also demonstrate that macrophage-derived foam cells isolated from rabbit atherosclerotic lesions exhibit a resistance to high density lipoprotein (HDL)-mediated cholesterol efflux along with reduced levels of NCEH activity compared to lipid-loaded mouse peritoneal macrophages. Thus, low level expression of HSL may partially account for the reduced NCEH activity observed in arterial foam cells isolated from atherosclerosis-susceptible species.

Aged↗

PubMed2000

Monocyte-endothelial cell coculture enhances infection of endothelial cells with Chlamydia pneumoniae.

To determine the mechanism(s) by which Chlamydia pneumoniae homes to and establishes persistent infection in atheromatous lesions, the effect of the interaction of monocytes/macrophages (U937 cells) with human umbilical vein endothelial cells (HUVECs) and transformed human arterial endothelial cells (HMEC-1s) on the susceptibility of endothelial cells to infection with C. pneumoniae was investigated. Infection was enhanced 4.7-fold (HUVECs) and 4.4-fold (HMEC-1s) after coculture at monocyte-to-endothelial cell ratios of 5 and 2.5, respectively. U937 cells also directly transmitted infection to the endothelial cells, and addition of U937 cell-conditioned media dose-dependently enhanced the infectivity 2.0- to 2.5-fold. The stimulation of infectivity was specific to endothelial cells, because coculturing of monocytes with epithelial cells did not enhance the susceptibility of epithelial cells to infection. The susceptibility of endothelial cells to infection with C. trachomatis and C. psittaci was not enhanced by the monocyte-derived factor(s).

Cell Communication↗

PubMed2000

Chlamydia, inflammation, and atherogenesis.

Atherosclerotic lesions are initiated and progress largely as a result of a chronic, fibroproliferative, inflammatory response. This review discusses how Chlamydia pneumoniae could conceivably contribute to this chronic inflammatory response and reports on recent in vivo and in vitro studies. In vivo studies in mice demonstrate that C. pneumoniae infection is disseminated to the artery wall following infection in the lung by alveolar macrophages. Recent in vitro studies show that infected U937 cells can directly transfer infection to endothelial cells and can indirectly increase the susceptibility of endothelial cells to C. pneumoniae infection. Loading of RAW 264.7 cells with modified forms of low-density lipoprotein increases the resistance of the cells to C. pneumoniae infection and also increases the susceptibility to the combined toxic effects of modified lipids and C. pneumoniae infection.

Animals↗

PubMed2000

Detection of dissection and remodeling of atherosclerotic lesions in rabbits after balloon angioplasty by magnetic-resonance imaging.

OBJECTIVE: To assess the usefulness of magnetic-resonance imaging (MRI) for monitoring acute changes after angioplasty of preexisting lesions in rabbits with basal lesions similar to those observed in humans. METHODS: A combination of Fogarty balloon injury (1 week after initiation of diet) and a mildly hypercholesterolemic diet (0.2% cholesterol and 5% peanut oil) was used to promote the rapid formation of atherosclerotic lesions in 16 New Zealand white rabbits. After 5 months of the diet, angioplasty was performed on these lesions with a Grüntzig catheter in both iliac arteries and the abdominal aorta. MRI was used to monitor the initial formation of lesions after 3 and 5 months of the diet, and 2 days, 2 weeks, and 1 and 2 months after angioplasty. RESULTS: The combination of early Fogarty injury and mildly hypercholesterolemic diet induced fibroproliferative lesions similar to type Vb atherosclerotic lesions seen in humans. Angioplasty induced deep dissections at the shoulders of lesions in the majority of animals. These dissections often extended into the media. The cellular, proliferative response after angioplasty was localized and limited to sites of dissection. A significant increase in area of arterial wall was observed after angioplasty at sites of dissection without any loss of lumen. In contrast, proximal and distal to the sites of injury, there was no change in wall area but a transient reduction in lumen area. CONCLUSIONS: Comparison of MRI results with histology confirmed that changes in the wall and lumen, including small linear dissections in the lesions and arterial remodeling, are detectable by MRI.

Angioplasty, Balloon↗

PubMed2000

Effect of Chlamydia trachomatis infection on atherosclerosis in apolipoprotein E-deficient mice.

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.

Animals↗

PubMed2000

Chlamydia pneumoniae induces inflammatory changes in the heart and aorta of normocholesterolemic C57BL/6J mice.

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.

Animals↗

PubMed2000

Advanced atherosclerotic lesions in the innominate artery of the ApoE knockout mouse.

Most previous studies of atherosclerosis in hyperlipidemic mouse models have focused their investigations on lesions within the aorta or aortic sinus in young animals. None of these studies has demonstrated clinically significant advanced lesions. We previously mapped the distribution of lesions throughout the arterial tree of apolipoprotein E knockout (apoE(-/-)) mice between the ages of 24 and 60 weeks. We found that the innominate artery, a small vessel connecting the aortic arch to the right subclavian and right carotid artery, exhibits a highly consistent rate of lesion progression and develops a narrowed vessel characterized by atrophic media and perivascular inflammation. The present study reports the characteristics of advanced lesions in the innominate artery of apoE(-/-) mice aged 42 to 60 weeks. In animals aged 42 to 54 weeks, there is a very high frequency of intraplaque hemorrhage and a fibrotic conversion of necrotic zones accompanied by loss of the fibrous cap. By 60 weeks of age, the lesions are characterized by the presence of collagen-rich fibrofatty nodules often flanked by lateral xanthomas. The processes underlying these changes in the innominate artery of older apoE(-/-) mice could well be a model for the critical processes leading to the breakdown and healing of the human atherosclerotic plaque.

Age Factors↗

PubMed2000

An overview of the evolution of the atherosclerotic plaque: from fatty streak to plaque rupture and thrombosis.

Today, there is a wealth of information concerning the chronology of the cellular and molecular events associated with the development of cardiovascular diseases. It is now clear that atherosclerosis is largely a result of a dysregulated fibroproliferative inflammatory response [1]. Treatment of cardiovascular disease is rapidly adapting to this new knowledge and the future holds great potential for preventing the disease by blocking the process at multiple stages. This short review provides an overview of the evolution of the atherosclerotic plaque. It focuses on three basic stages of the disease processes: initiation of the fatty streak, transition of the fatty streak to an atheroma, and progression and destabilization of the lesions leading to plaque rupture and occlusive thrombosis. It includes a discussion of the molecular and cellular biology of the atherogenic process with an emphasis on key molecular mediators of the disease process and provides three tables which list examples of some of the key molecular mediators and the stages in which they are purported to play a role.

Animals↗

PubMed1999

Initiation of hyperinsulinemia and hyperleptinemia is diet dependent in C57BL/6 mice.

C57BL/6 female mice were fed high fat diets containing different types of carbohydrate (sucrose or corn starch) and contents of cholesterol (0.03 % or 1 %) to identify early metabolic changes leading to increases in leptin levels and eventual insulin resistance. Under identical dietary fat conditions, type of carbohydrate and cholesterol content contributed to the timing of leptin increases. Mice fed a high-fat, high-sucrose diet showed early (4 weeks) and robust increases in circulating insulin and leptin levels (2-fold and 5-fold, respectively). In contrast, mice fed this diet with added cholesterol or with sucrose substituted by corn starch led to marked delays (8-10 weeks) in the elevations of insulin and leptin, although body weight gains were nearly identical among test diet groups. Thus, sucrose in combination with saturated fat played a specific role in initiating early metabolic changes associated with elevated leptin and insulin levels. Because leptin levels were most reflective of changes in insulin, our data support a role for insulin in determining plasma leptin levels in mice.

Animals↗

PubMed1999

Chlamydia pneumoniae infection accelerates the progression of atherosclerosis in apolipoprotein E-deficient mice.

Accumulating evidence supports an association between Chlamydia pneumoniae infection and atherosclerosis. To determine whether there is a causal relationship, the effects of chronic infection with C. pneumoniae on the development of atherosclerosis in apolipoprotein E (apoE)-deficient mice were evaluated. Eight-week-old male apoE-deficient mice were inoculated intranasally with C. pneumoniae three times, at 8, 9, and 10 weeks of age. The combined area of atherosclerotic lesions in the lesser curvature of the aortic arch was measured en face by computer-assisted morphometry. The lesion area was 2.4-fold greater (P=.05) at 16 weeks of age and 1.6-fold greater (P=.05) at 20 weeks of age in infected mice than in control mice. There were no differences in total plasma cholesterol levels between groups. This study demonstrates that C. pneumoniae infection accelerates the progression of atherosclerosis in the aortic arch of apoE-deficient mice.

Animals↗

PubMed1998

Inflammation, lipids, and free radicals: lessons learned from the atherogenic process.

This review focuses on the question of how oxidative stress in cells populating atherosclerotic lesions stimulates gene expression, cell proliferation, and cell death, and how these events contribute to the initiation, progression, and destablization of the lesions. It is hypothesized that oxidative stress in endothelial cells, macrophages, and smooth muscle cells occurs as a result of the depletion of the cellular content of reduced glutathione. Glutathione becomes oxidized in response to the accumulation of oxidized lipids, the formation of reactive oxygen species released from the mitochondria and generated as part of the activation-induced respiratory burst, and the generation of nitric oxide, peroxynitrite, and thiol radicals. Both in vitro and in vivo evidence suggests that these cells can take up modified lipoproteins that become trapped within the artery wall leading to the overaccumulation of oxidized fatty acids and oxidized forms of cholesterol. The cells also generate oxidized lipids via the activity of lipoxygenases, cyclooxygenases, and myeloperoxidase. A sublethal oxidative stress can activate redox-sensitive kinase cascades and transcription factors such as NFB and AP-1, with resulting increases in the expression of factors associated with an inflammatory response and cellular proliferation. There is also accumulating evidence that suggests that oxidative stress may be associated with the induction of cell death either via stimulation of apoptosis and/or necrosis and that increased cell death contributes to the formation of a necrotic core, the hallmark of an advanced, unstable lesion.

Apoptosis↗