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Biomedical subjects

A Daugherty

Publications and source records attributed to A Daugherty.

At least 19 recordsLinked to original sources
PubMed2001

Development of poly-(D,L-lactide--coglycolide) microsphere formulations containing recombinant human vascular endothelial growth factor to promote local angiogenesis.

Although preclinical animal studies have demonstrated the utility of recombinant human vascular endothelial growth factor (rhVEGF) in promoting neovascularization in regions of ischemia, rhVEGF systemic administration did not provide clinical benefit to patients in recent placebo-controlled Phase II clinical trials. The amount of rhVEGF localized in the ischemic region after systemic administration is minimal and does not persist for more than 1 day. A greater persistence of rhVEGF at the region of ischemia may provide an increased angiogenesis with the eventual formation of patent blood vessels to restore nourishment to the tissues. We sought to develop a formulation of rhVEGF in poly(D,L-lactide--co-glycolide) (PLG) microspheres that would provide a continuous local delivery of intact protein. A stable formulation of rhVEGF for encapsulation contained a small amount of a stabilizing sugar, trehalose. Addition of excess trehalose increased the rate of release from the PLG. In addition, PLG with free acid end groups appeared to retard the initial release of rhVEGF by associating with it through ionic interactions at the positively charged heparin binding domain. rhVEGF was released continuously for 21 days with a very low (less than 10%) initial burst. The released rhVEGF aggregated and hydrolyzed over time and lost heparin affinity but not receptor affinity. The compression molding of rhVEGF PLG microspheres into disks yielded formulations with a low initial release and a lag of 10 days followed by complete release. The PLG microsphere formulations were assessed in the corneal implant model of angiogenesis and generated a dose-dependent angiogenic response. These formulations were also administered intravitreally and subretinally, generating local neovascularization comparable to the human disease states, vitroretinopathy and age-related macular degeneration, respectively. The rhVEGF PLG formulations may increase local angiogenesis without systemic side effects and may also be useful in the development of ocular disease models.

Animals↗
PubMed2001

Sidestream cigarette smoke accelerates atherogenesis in apolipoprotein E-/- mice.

Epidemiological studies have strongly implicated active and passive smoking with increased risk of cardiovascular diseases. The present study was performed to determine if exposure to sidestream cigarette smoke (SSCS), a surrogate of environmental tobacco smoke, promotes atherogenesis in a mouse model of human atherosclerosis. Female ApoE-deficient mice, maintained on a Western diet, were exposed to SSCS in a whole-body exposure chamber for a total of 6 h each day, 5 days a week for 7, 10 and 14 weeks. Animals exposed to filtered ambient air served as controls. Elevated concentrations of blood carboxyhemoglobin and pulmonary CYP1A1 ascertained effective exposure of animals to SSCS. There were no consistent changes in serum concentrations of cholesterol between control and SSCS-exposed mice. Morphometric assessment of grossly discernible lesions covering the intimal area of aorta showed remarkable increases in SSCS-exposed mice at all three exposure durations studied. Increases in the lesion area defined by en face measurements were accompanied by parallel increases in the levels of esterified and unesterified cholesterol in the aortic tissues of SSCS mice. These results clearly demonstrate promotion of atherosclerotic lesion development by tobacco smoke in an atherosclerosis-susceptible mouse model.

Animals↗
PubMed2001

Freunds adjuvant alone is antiatherogenic in apoE-deficient mice and specific immunization against TNFalpha confers no additional benefit.

TNFalpha participates in the pathogenesis of atherosclerosis. The effect of immunization against TNFalpha on development of advanced vascular lesions in atherosclerosis-susceptible apoE-deficient mice was investigated. At 5-7 weeks of age, animals received immunization with either Freunds adjuvant and a recombinant antigenic TNFalpha molecule (TNF106), Freunds adjuvant alone, or no immunization. All mice received a Western-type high-fat diet for 12 weeks. Aortic sinus lesion area was determined by microscopic morphometry, the total aortic arch cholesterol content was determined by gas chromatography, and antibodies against TNFalpha, malondialdehyde-modified low density lipoprotein, or heat shock protein 60, were assessed by ELISAs. Immunization with TNF106 induced high-titered circulating antibodies against TNFalpha (n=23), and these antibodies were not detected in mice immunized with Freunds adjuvant alone (n=22), or in non-immunized control animals (n=25). After 12 weeks, the atherosclerotic lesion size was significantly reduced in immunized animals, whether they had been immunized with TNF106 or Freunds adjuvant alone, and the total lesional cholesterol content was decreased in mice immunized with TNF106. There were no correlations between circulating antibody titers and plaque size, total aortic arch cholesterol content, or plasma lipid levels, respectively. Administration of Freunds adjuvant alone can thus reduce formation of mature atherosclerotic lesions in apoE-deficient mice and this response is not modified by specific immunization against TNFalpha.

Animals↗
PubMed2001

Emerging protein delivery methods.

The efficient and safe delivery of therapeutic proteins is the key to commercial success and, in some cases, the demonstration of efficacy in current and future biotechnology products. Numerous delivery technologies and companies have evolved over the past year. To critically evaluate the available options, each method must be assessed in terms of how easily it can be manufactured, impact on protein quality, bioavailability, and toxicity. Recent advances in depot delivery systems have, for the most part, overcome all of these obstacles except for complex and costly manufacturing. On the other hand, pulmonary delivery usually involves efficient manufacturing, but low protein bioavailability resulting in higher doses compared with injections. Although recent advances in transdermal and oral delivery have been significant, both of these delivery routes require logarithmic increases in bioavailability to make them viable candidates for commercialization. In the next few years, protein delivery for commercial products will probably be limited to injection devices, depot systems and pulmonary administration.

Biological Availability↗
PubMed2001

Antagonism of AT2 receptors augments angiotensin II-induced abdominal aortic aneurysms and atherosclerosis.

1. We have recently demonstrated that chronic infusion of Angiotensin II into apoE-/- mice promotes the development of abdominal aortic aneurysms. To determine the involvement of specific Angiotensin II receptors in this response, we co-infused Angiotensin II (1000 ng kg(-1) min(-1) for 28 days) with losartan (30 mg kg(-1) day(-1)) or PD123319 (3 mg kg(-1) day(-1)) to antagonize AT1 and AT2 receptors, respectively. 2. Infusion of Angiotensin II promoted the development of abdominal aortic aneurysms in 70% of mature female apoE-/- mice. The formation of aortic aneurysms was totally inhibited by co-infusion of Angiotensin II with losartan (30 mg kg(-1) day(-1); P=0.003). In contrast, the co-infusion of Angiotensin II with PD123319 resulted in a marked increase in the incidence and severity of aortic aneurysms. 3. To determine whether AT2 antagonism also promoted Angiotensin II-induced atherosclerosis, Angiotensin II was infused into young female apoE-/- mice that had little spontaneous atherosclerosis. In these mice, co-infusion of PD123319 led to a dramatic increase in the extent of atherosclerosis. This increase was associated with no change in plasma lipid concentrations and only transient and modest increases in blood pressure during co-infusion with PD123319. 4. While antagonism of AT1 receptors totally prevented the formation of aneurysms, antagonism of AT2 receptors promoted a large increase in the severity of Angiotensin II-induced vascular pathology.

Angiotensin II↗
PubMed2001

Interleukin 4 induces transcription of the 15-lipoxygenase I gene in human endothelial cells.

The reticulocyte-type 15-lipoxygenase (15-LO-I) has been implicated in atherogenesis because of its capability of oxidizing low density lipoprotein. Therefore, we investigated the expression of the 15-LO-I gene in human umbilical vein endothelial cells (HUVEC). Nonactivated HUVEC did not exhibit detectable 15-LO-I mRNA. However, exposure of the cells to interleukin 4 (IL-4) induced the transcription of the 15-LO-I gene in a time- and concentration-dependent manner. Interestingly, this induction was not paralleled by a concomitant production of the functional 15-LO-I enzyme, as indicated by activity assays and immunoblotting. To gain more information about the mechanism of the induction process, we investigated IL-4-dependent activation of nuclear transcription factors for which binding sites were previously identified in the 5'-flanking region of the human 15-LO-I gene. Electrophoretic mobility shift assays revealed that IL-4 can activate signal transducer and activator of transcription 6, activator protein 2, GATA motif-binding transcription factor 1, nuclear factor 1, and SP-1 in HUVEC in a time- and concentration-dependent manner. Activation of these transcription factors was observed as early as 30 min after cytokine exposure. These data indicate that IL-4 upregulates the transcription of the 15-LO-I gene in human vascular endothelial cells, and this process may involve the activation of several nuclear transcription factors. The lack of active 15-LO-I protein in the presence of functional 15-LO-I mRNA suggests additional regulatory elements of 15-LO expression at posttranscriptional levels.

Arachidonate 15-Lipoxygenase↗
PubMed2001

Macrophage-specific expression of class A scavenger receptors enhances granuloma formation in the absence of increased lipid deposition.

Class A scavenger receptors (SR-A) have several proposed functions that could impact atherosclerosis and inflammatory processes. To define the function of SR-A in vivo, we created C57BL/6 transgenic mice that expressed bovine SR-A under the control of the restricted macrophage promoter, lysozyme (lyso-bSR-A). bSR-A mRNA was present in cultured peritoneal macrophages of transgenic mice and tissues that contain significant macrophages including spleen, lung, and ileum. Functional overexpression of SR-A was demonstrated in peritoneal macrophages both by augmented cholesterol ester deposition in response to AcLDL and enhanced adhesion in transgenic mice compared with nontransgenic littermates. To determine whether macrophage-specific expression of bSR-A regulated inflammatory responses, granulomas were generated by subcutaneous injection of carrageenan. Granuloma size was significantly increased in lyso-bSR-A transgenic mice compared with wild-type littermates [421 +/- 51 mg (n = 11) vs. 127 +/- 22 mg (n = 10), P < 0.001]. However, the larger granulomas in lyso-bSR-A transgenic mice were only associated with an increase in unesterified cholesterol, and not cholesterol esters. Furthermore, granulomas from transgenic mice had an increase in the number of macrophages within the tissue.Therefore, macrophage expression of bSR-A increased presence of this cell type in granulomas without enhancing the deposition of cholesterol esters, consistent with a role of the adhesive property of the protein.

Animals↗
PubMed2000

Macrophage colony-stimulating factor rapidly enhances beta-migrating very low density lipoprotein metabolism in macrophages through activation of a Gi/o protein signaling pathway.

Previous studies have examined lipoprotein metabolism by macrophages following prolonged exposure (>24 h) to macrophage colony-stimulating factor (M-CSF). Because M-CSF activates several signaling pathways that could rapidly affect lipoprotein metabolism, we examined whether acute exposure of macrophages to M-CSF alters the metabolism of either native or modified lipoproteins. Acute incubation of cultured J774 macrophages and resident mouse peritoneal macrophages with M-CSF markedly enhanced low density lipoproteins (LDL) and beta-migrating very low density lipoproteins (beta-VLDL) stimulated cholesteryl [(3)H]oleate deposition. In parallel, M-CSF treatment increased the association and degradation of (125)I-labeled LDL or beta-VLDL without altering the amount of lipoprotein bound to the cell surface. The increase in LDL and beta-VLDL metabolism did not reflect a generalized effect on lipoprotein endocytosis and metabolism because M-CSF did not alter cholesterol deposition during incubation with acetylated LDL. Moreover, M-CSF did not augment beta-VLDL cholesterol deposition in macrophages from LDL receptor (-/-) mice, indicating that the effect of M-CSF was mediated by the LDL receptor. Incubation of macrophages with pertussis toxin, a specific inhibitor of G(i/o) protein signaling, had no effect on cholesterol deposition during incubation with beta-VLDL alone, but completely blocked the augmented response promoted by M-CSF. In addition, incubation of macrophages with the direct G(i/o) protein activator, mastoparan, mimicked the effect of M-CSF by enhancing cholesterol deposition in cells incubated with beta-VLDL, but not acetylated LDL. In summary, M-CSF rapidly enhances LDL receptor-mediated metabolism of native lipoproteins by macrophages through activation of a G(i/o) protein signaling pathway. Together, these findings describe a novel pathway for regulating lipoprotein metabolism.

Androstadienes↗
PubMed2000

Exogenous interferon-gamma enhances atherosclerosis in apolipoprotein E-/- mice.

A role for interferon-gamma (IFN-gamma) has been implied in the atherogenic process. To determine whether exogenously administered IFN-gamma exerts an effect on the development of atherosclerosis, we intraperitoneally administered either recombinant IFN-gamma (100 U/g body weight) or phosphate buffered saline daily for 30 days to atherosclerosis-susceptible apolipoprotein E-/- mice (16-week-old male mice, n = 11 per group) fed a normal diet. Atherosclerotic lesion size was quantified in the ascending aorta. The number of T lymphocytes and major histocompatibility complex (MHC) class II-positive cells within lesions were also quantified in this region. IFN-gamma administration reduced serum cholesterol concentrations by 15% (P = 0.02). For both groups, the majority of cholesterol was present in very low density lipoproteins, which were modestly reduced in mice receiving IFN-gamma. Despite the decrease in serum cholesterol concentrations, IFN-gamma injections significantly increased lesion size twofold compared to controls (119,980 +/- 18, 536 vs. 59,396 +/- 20,017 micrometer(2); P = 0.038). IFN-gamma also significantly increased the mean number of T lymphocytes (19 +/- 4 vs. 7 +/- 1 cells; P = 0.03) and MHC class II-positive cells (10 +/- 3 vs. 3 +/- 1 cells; P = 0.04) within lesions. These data lend further support to a pro-atherogenic role of IFN-gamma.

Animals↗
PubMed2000

Angiotensin II promotes atherosclerotic lesions and aneurysms in apolipoprotein E-deficient mice.

Increased plasma concentrations of angiotension II (Ang II) have been implicated in atherogenesis. To examine this relationship directly, we infused Ang II or vehicle for 1 month via osmotic minipumps into mature apoE(-/-) mice. These doses of Ang II did not alter arterial blood pressure, body weight, serum cholesterol concentrations, or distribution of lipoprotein cholesterol. However, Ang II infusions promoted an increased severity of aortic atherosclerotic lesions. These Ang II-induced lesions were predominantly lipid-laden macrophages and lymphocytes; moreover, Ang II promoted a marked increase in the number of macrophages present in the adventitial tissue underlying lesions. Unexpectedly, pronounced abdominal aortic aneurysms were present in apoE(-/-) mice infused with Ang II. Sequential sectioning of aneurysmal abdominal aorta revealed two major characteristics: an intact artery that is surrounded by a large remodeled adventitia, and a medial break with pronounced dilation and more modestly remodeled adventitial tissue. Although no atherosclerotic lesions were visible at the medial break point, the presence of hyperlipidemia was required because infusions of Ang II into apoE(+/+) mice failed to generate aneurysms. These results demonstrate that increased plasma concentrations of Ang II have profound and rapid effects on vascular pathology when combined with hyperlipidemia, in the absence of hemodynamic influences.

Angiotensin II↗
PubMed2000

Interleukin-4 augments acetylated LDL-induced cholesterol esterification in macrophages.

Activated subpopulations of lymphocytes and mast cells have been detected in atherosclerotic lesions. Interleukin-4 (IL-4) is a prominent cytokine released during activation of both cell types and its transcripts have been detected in both human and mouse atherosclerotic lesions. To define whether this local release of IL-4 influences macrophage lipid metabolism, we examined the effects of this cytokine on intracellular cholesterol esterification during incubation with modified low density lipoprotein (LDL). IL-4 greatly augmented cholesterol esterification induced by acetylated LDL (AcLDL) in both mouse peritoneal macrophages and the murine macrophage cell line, J774. This augmentation was maximal at a concentration of 1 ng/ml after incubation for 48 h. This was not a generalized effect on lipoprotein metabolism as IL-4 had no effect on cholesterol esterification in the presence of either LDL or beta-VLDL. Determination of binding isotherms demonstrated that IL-4 increased the number of cell surface binding sites for AcLDL. The IL-4-augmented AcLDL-induced cholesterol esterification was attenuated by the scavenger receptor class A (SR-A) antagonist, fucoidan, and the anti-mouse SR-A monoclonal antibody, 2F8. These data, combined with the known receptor specificity of AcLDL interactions, imply a role of SR-A in the IL-4 induced responses. Two cytokines that have been demonstrated previously to down-regulate SR-A, TNF-alpha and TGF-beta, antagonized the IL-4-induced augmentation of cholesterol esterification. Therefore, local release of IL-4 within atherosclerotic lesions could have a profound effect on macrophage lipid metabolism and the subsequent atherogenic process.

Animals↗
PubMed2000

Regulation of acetylated low density lipoprotein uptake in macrophages by pertussis toxin-sensitive G proteins.

Class A scavenger receptors (SR-A) mediate the uptake of modified low density lipoprotein (LDL) by macrophages. Although not typically associated with the activation of intracellular signaling cascades, results with peritoneal macrophages indicate that the SR-A ligand acetylated LDL (AcLDL) promotes activation of cytosolic kinases and phospholipases. These signaling responses were blocked by the treatment of cells with pertussis toxin (PTX) indicating that SR-A activates G(i/o)-linked signaling pathways. The functional significance of SR-A-mediated G(i/o) activation is not clear. In this study, we investigated the potential role of G(i/o) activation in regulating SR-A-mediated lipoprotein uptake. Treatment of mouse peritoneal macrophages with PTX decreased association of fluorescently labeled AcLDL with cells. This inhibition was dependent on the catalytic activity of the toxin confirming that the decrease in AcLDL uptake involved inhibiting G(i/o) activation. In contrast to the inhibitory effect on AcLDL uptake, PTX treatment did not alter beta-VLDL-induced cholesterol esterification or deposition of cholesterol. The ability of polyinosine to completely inhibit AcLDL uptake, and the lack of PTX effect on beta-VLDL uptake, demonstrated that the inhibitory effect is specific for SR-A and not the result of non-specific effects on lipoprotein metabolism. Despite having an effect on an SR-A-mediated lipoprotein uptake, there was no change in the relative abundance of SR-A protein after PTX treatment. These results demonstrate that activation of a PTX-sensitive G protein is involved in a feedback process that positively regulates SR-A function.

Acetylation↗
PubMed2000

Polymorphism of class A scavenger receptors in C57BL/6 mice.

Scavenger receptors class A (SR-A) have been hypothesized to regulate the development of atherosclerotic lesions through recognition of modified low density lipoprotein (LDL) and macrophage adhesion to substrata. Supporting data have been collected from studies using the monoclonal antibody 2F8, an antibody developed from the BALB/c strain-derived macrophage cell line, RAW.264. Although 2F8 immunostained both cultured peritoneal macrophages (MPM) and thymic macrophages from Swiss, BALB/c, and DBA/2 mice, no immunostaining was detected in cells and tissues from C57BL/6 mice, one of the most commonly used atherosclerosis-susceptible mouse strains. Similarly, 2F8 detected SR-A protein in MPM by Western blotting in all strains except C57BL/6. However, a guinea pig antiserum developed to a fusion protein of the extracellular SR-A domain detected appropriately sized bands in all strains. Incubation with 2F8 antagonized acetylated low-density lipoprotein (AcLDL)-induced cholesterol esterification in MPM from BALB/c, Swiss, and DBA/2 strains but had no effect on MPM from C57BL/6 mice. Sequencing of SR-A cDNA from C57BL/6 mice demonstrated complete identity with published sequence in the collagen-like domain. However, four single-residue substitutions were noted in the alpha-helical coiled-coil domain. Site-directed mutagenesis demonstrated that a single substitution (L168S) in this domain accounted for the loss of 2F8 immunoreactivity. Differing reactivities toward a commonly used monoclonal antibody were used to identify polymorphism of SR-A in C57BL/6 mice.

Animals↗
PubMed1999

Chronic angiotensin II infusion promotes atherogenesis in low density lipoprotein receptor -/- mice.

The purpose of this study was to determine the effect of chronic angiotensin II (AngII) infusion on the severity of the atherogenic process in low density lipoprotein (LDL) receptor -/- mice with established lesions. LDL receptor -/- mice receiving a diet enriched in cholesterol, saturated fat, and cholate, were infused with saline or AngII (500 ng/kg/min) for 28 days. Systolic blood pressure increased in LDL receptor -/- mice following 7 days of AngII infusion, followed by a decline to baseline levels at 28 days, despite continued AngII infusion. Serum cholesterol was not influenced by AngII infusion in LDL receptor -/- mice; however, serum triglyceride concentrations were reduced significantly in LDL receptor -/- mice receiving AngII. The percent of intimal surface area covered by lesion was not increased in LDL receptor -/- mice receiving AngII; however, the content of cholesterol (esterified and unesterified) in lesions of the arch, thoracic, and abdominal aorta was significantly increased in those mice infused with AngII. Of note, in 20% of the LDL receptor -/- mice receiving AngII, large aneurysms were found in the abdominal aorta. Aneurysms appeared as breaks in the media and surrounding tissue of the vessel wall, encompassing amorphous and acellular masses with patches of thrombotic material. These results demonstrate that chronic infusion of AngII promotes the atherogenic processes in LDL receptor -/- mice, manifest as increases in lesion cholesterol content. Effects of AngII to promote atherogenesis were apparent at doses which did not markedly elevate systolic pressure. Importantly, infusion of AngII in LDL receptor -/- mice resulted in the development of aortic aneurysms.

Angiotensin II↗
PubMed1998

Absence of T lymphocyte-derived cytokines fails to diminish macrophage 12/15-lipoxygenase expression in vivo.

IL-4 and IL-13 are the only known activators of 15-lipoxygenase (LO) expression in cultured macrophages. To determine whether these lymphocyte-derived cytokines regulate 15-LO expression in vivo, the abundance of the murine homologue (12/15-LO) was assessed in peritoneal macrophages from immune-deficient strains of mice. Macrophages were harvested from recombinase activator gene (RAG)-2-/- mice that do not develop mature lymphocytes and cannot secrete activation-dependent cytokines. Unexpectedly, 12/15-LO protein and activity were significantly increased in peritoneal macrophages from RAG-2-/- mice compared with strain-matched controls. This increase was related to phenotypic differences between cells from RAG-2+/+ and RAG-2-/- mice. After 3 h in culture, RAG-2+/+ macrophages were of two distinct sizes, with only the larger cells immunostaining for 12/15-LO. However, all RAG-2-/- cells were distributed in the large size range, and all were immunoreactive for the enzyme. The activation of 12/15-LO expression appears to be related to prolonged residence within the peritoneum, since there were fewer resident peritoneal macrophages in RAG-2-/- than in RAG-2+/+ mice, and newly recruited macrophages elicited by the administration of Sephacryl to RAG-2-/- mice did not immunostain for 12/15-LO. To determine whether 12/15-LO expression was due to IL-4 or IL-13 from nonlymphoid cells, the abundance of the enzyme was quantified in peritoneal macrophages from STAT6-/-mice that have attenuated responses to both cytokines. STAT6 deficiency did not influence the abundance of the protein in macrophages. Therefore, neither IL-4 nor IL-13 secretion is a requirement for macrophage 15-LO expression in vivo.

Animals↗
PubMed1998

A specific 15-lipoxygenase inhibitor limits the progression and monocyte-macrophage enrichment of hypercholesterolemia-induced atherosclerosis in the rabbit.

Oxidant signalling and lipoprotein oxidation may play important roles in atherosclerotic lesion development. Given coincident localization of 15-lipoxygenase (15-LO), stereospecific products of 15-LO and epitopes of modified LDL in atherosclerotic lesions, we hypothesized that inhibition of 15-LO by PD146176, an inhibitor of 15-LO with an IC50 in cells or isolated enzyme of 0.5-0.8 microM, may limit atherosclerotic lesion development through regulation of monocyte-macrophage enrichment. Rabbits exposed to chronic endothelial denudation of the iliac-femoral artery were meal-fed a 0.25% cholesterol (C), 3% peanut oil (PNO), 3% coconut oil (CNO) diet twice daily with and without 175 mg/kg PD146176 for 12 weeks. In a second study, atherosclerotic lesions were pre-established in rabbits through chronic endothelial denudation and meal-fed a 0.5% C, 3% PNO, 3% CNO diet for 9 weeks and a 0% C/fat diet for 6 weeks prior to an 8 week administration of PD146176 at 175 mg/kg, q.d. Plasma total and lipoprotein cholesterol exposure were similar in control and PD146176-treated animals in both studies but PD146176 increased plasma triglyceride exposure 2- to 4-fold. Plasma PD146176 concentrations ranged from 99 to 214 ng/ml at 2 h post-dose. In the progression study, the iliac-femoral monocyte-macrophage area was reduced 71%, cross-sectional lesion area was unchanged and cholesteryl ester (CE) content was reduced 63%. In the regression study, size and macrophage content of iliac-femoral, fibrous plaque-like lesions were decreased 34%, CE content was reduced 19% and gross extent of thoracic aortic lesions were reduced 41%. We conclude that PD146176 can limit monocyte macrophage enrichment of atherosclerotic lesions and can attenuate development of fibrofoamy and fibrous plaque lesions in the absence of changes in plasma total or lipoprotein cholesterol concentrations.

Animals↗