Development Of Early Atherosclerotic Lesions Research Articles

CABG MODELS FLOW SIMULATION STUDY ON THE EFFECTS OF VALVE REMNANTS IN THE VENOUS GRAFT

Venous valves and sinuses are frequently observed in vein grafts in the coronary artery bypass grafts (CABG). However, from the biomedical engineering viewpoint, vein grafts are always assumed as smooth tubes in the existing simulations, and no effort has been made to investigate the effects of jaggedness of the graft inner wall due to the valve cusps remnants and valve sinus (in case of valve-stripped saphenous vein (SV) grafts) on the blood flow patterns and hemodynamic parameters (HPs). In this paper, the effects of the inner surface irregularities of a vein graft on the blood flow is investigated in the graft as well as in the distal anastomotic region, with a more realistic geometry of valve-stripped SV, by means of numerical simulation of pulsatile, Newtonian blood flow. The simulation results demonstrate that the valve remnants and sinuses cause disturbances in the flow field within the graft (due to vortices formation within the valve sinuses) and undesirable distribution of HPs, which can result in early atherosclerotic lesion development in the graft.

Angiotensin-converting enzyme 2 attenuates atherosclerotic lesions by targeting vascular cells

Angiotensin-converting enzyme 2 (ACE2) is a newly discovered homolog of ACE whose actions oppose those of angiotensin II (AngII). However, the underlying mechanisms by which ACE2 effectively suppresses early atherosclerotic lesions remain poorly understood. Here, we show, both in vitro and in vivo, that ACE2 inhibited the development of early atherosclerotic lesions by suppressing the growth of vascular smooth muscle cells (VSMCs) and improving endothelial function. In a relatively large cohort animal study (66 rabbits), aortic segments transfected by Ad-ACE2 showed significantly attenuated fatty streak formation, neointimal macrophage infiltration, and alleviation of impaired endothelial function. Segments also showed decreased expression of monocyte chemoattractant protein 1, lectin-like oxidized low-density lipoprotein receptor 1, and proliferating cell nuclear antigen, which led to the delayed onset of atherosclerotic lesions. At the cellular level, ACE2 significantly modulated AngII-induced growth and migration in human umbilical vein endothelial cells and VSMCs. The antiatherosclerotic effect of ACE2 involved down-regulation of the ERK-p38, JAK-STAT, and AngII-ROS-NF-kappaB signaling pathways and up-regulation of the PI3K-Akt pathway. These findings revealed the molecular mechanisms of the antiatherosclerotic activity of ACE2 and suggested that modulation of ACE2 could offer a therapeutic option for treating atherosclerosis.

LOX-1: Luring ox-LDL into the arterial wall

LOX-1: Luring ox-LDL into the arterial wall

Short-term delivery of anti-PlGF antibody delays progression of atherosclerotic plaques to vulnerable lesions

Placental growth factor (PlGF), a homologue of vascular endothelial growth factor, is a pleiotropic cytokine with a pro-inflammatory activity. Previous gene-inactivation studies revealed that the loss of PlGF delays atherosclerotic lesion development and inhibits macrophage infiltration, but the activity of an anti-PlGF antibody (alphaPlGF mAb) has not been evaluated yet. We characterized the potential of short-term delivery of alphaPlGF mAb in inhibiting lesion development in ApoE-deficient mice (apoE(-/-)) and in CD4:TGFbetaRII(DN) x apoE(-/-) mice, a more severe atherosclerosis model. Short-term treatment of alphaPlGF mAb reduces early atherosclerotic plaque size and inflammatory cell infiltration in the lesion. These pharmacological alphaPlGF mAb results confirm previous genetic evidence that inhibition of PlGF slows down early atherosclerotic lesion development. Furthermore, the phenocopy of genetic and pharmacological loss-of-function strategies underscores that alphaPlGF acts by selectively neutralizing PlGF.

17β-Estradiol Prevents Early-Stage Atherosclerosis in Estrogen Receptor-Alpha Deficient Female Mice

Estrogen is atheroprotective and a high-affinity ligand for both known estrogen receptors, ERα and ERβ. However, the role of the ERα in early-stage atherosclerosis has not been directly investigated and is incompletely understood. ERα-deficient (ERα−/−) and wild-type (ERα+/+) female mice consuming an atherogenic diet were studied concurrent with estrogen replacement to distinguish the actions of 17β-estradiol (E2) from those of ERα on the development of early atherosclerotic lesions. Mice were ovariectomized and implanted with subcutaneous slow-release pellets designed to deliver 6 or 8 μg/day of exogenous 17β-estradiol (E2) for a period of up to 4 months. Ovariectomized mice (OVX) with placebo pellets (E2-deficient controls) were compared to mice with endogenous E2 (intact ovaries) and exogenous E2. Aortas were analyzed for lesion area, number, and distribution. Lipid and hormone levels were also determined. Compared to OVX, early lesion development was significantly (p < 0.001) attenuated by E2 with 55–64% reduction in lesion area by endogenous E2 and >90% reduction by exogenous E2. Compared to OVX, a decline in lesion number (2- to 4-fold) and lesser predilection (~4-fold) of lesion formation in the proximal aorta also occurred with E2. Lesion size, development, number, and distribution inversely correlated with circulating plasma E2 levels. However, atheroprotection was independent of ERα status, and E2 athero-protection in both genotypes was not explained by changes in plasma lipid levels (total cholesterol, triglyceride, and high-density lipoprotein cholesterol). The ERα is not essential for endogenous/exogenous E2-mediated protection against early-stage atherosclerosis. These observations have potentially significant implications for understanding the molecular and cellular mechanisms and timing of estrogen action in different estrogen receptor (ER) deletion murine models of atherosclerosis, as well as implications to human studies of ER polymorphisms and lipid metabolism. Our findings may contribute to future improved clinical decision-making concerning the use of hormone therapy.

Low vasa vasorum densities correlate with inflammation and subintimal thickening: Potential role in location—Determination of atherogenesis

Objectives To assess the role of coronary vasa vasorum (VV) spatial distribution in determining the location of early atherosclerotic lesion development. Methods and results Six, 3-month-old, female, crossbred swine were fed 2% high-cholesterol (HC) diet for 3 months prior to euthanasia. Six other pigs were fed normal diet (N) for the entire 6 months. Right coronary arteries were harvested and scanned intact with micro-CT (20 μm cubic-voxel-size). After scanning, randomly selected cross-sectional histological sections were stained for nuclear-factor kappaB (NF-κB), hypoxia-inducible factor-1alpha (HIF-1α), macrophages, von-Willebrand-factor, dihydroethidium (DHE), tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). The number of positive stained cells, as well as intima-to-media ratio, were compared with VV density (#/mm 2) obtained from micro-CT images (which closely matched the location of the histological sections) in each of four equal quadrants of the coronary vessel wall. In normal, as well as HC pigs, the number of NF-κB ( r = 0.73 and 0.70), HIF-1α ( r = 0.74 and 0.77), TNF-α ( r = 0.58 and 0.72) and IL-6 ( r = 0.70 and 0.72) positive cells as well as the expression of DHE (Kendall tau coefficient −0.64 and −0.63) inversely correlated with VV density. In HC the VV density also inversely correlated with intima/media ratios ( r = 0.65). Conclusions Our data suggest that low VV density territories within the coronary vessel wall are susceptible to hypoxia, oxidative stress and microinflammation and may therefore be starting points of early atherogenesis.

Molecular role of Cx37 in advanced atherosclerosis: A micro-array study

Recently, we showed that connexin37 (Cx37) protects against early atherosclerotic lesion development by regulating monocyte adhesion. The expression of this gap junction protein is altered in mouse and human atherosclerotic lesions; it is increased in macrophages newly recruited to the lesions and disappears from the endothelium of advanced plaques. To obtain more insight into the molecular role of Cx37 in advanced atherosclerosis, we used micro-array analysis for gene expression profiling in aortas of ApoE−/− and Cx37−/−ApoE−/− mice before and after 18 weeks of cholesterol-rich diet. Out of >15,000 genes, 106 genes were significantly differentially expressed in young mice before diet (P-value of <0.05, fold change of >0.7 or <−0.7, and intensity value >2.2 times background). Ingenuity pathway analysis (IPA) revealed differences in genes involved in cell-to-cell signaling and interaction, cellular compromise and nutritional disease. In addition, we identified 100 genes that were significantly perturbed after the cholesterol-rich diet. Similar to the analysis on 10-week-old mice, IPA revealed differences in genes involved in cell-to-cell signaling and interaction as well as to immuno-inflammatory disease. Furthermore, we found important changes in genes involved in vascular calcification and matrix degradation, some of which were confirmed at protein level by (immuno-)histochemistry. In conclusion, we suggest that Cx37 deficiency alters the global differential gene expression profiles in young mice towards a pro-inflammatory phenotype, which are then further influenced in advanced atherosclerosis. The results provide new insights into the significance of Cx37 in plaque calcification.

Oxidized LDL-Mediated Macrophage Survival Involves Elongation Factor-2 Kinase

Macrophage survival and proliferation is believed to be a contributing factor in the development of early atherosclerotic lesions. Oxidized low density lipoprotein (oxLDL), a key mediator in the pathogenesis of this disease, has been shown to block apoptosis in macrophages deprived of growth factor. In this report, we investigate the mechanism of oxLDL-mediated macrophage survival. OxLDL, but not native LDL (nLDL), induces an immediate and oscillatory increase in intracellular calcium ([Ca(2+)](i)). We also show that the calcium/calmodulin dependent kinase, eukaryotic elongation factor-2 kinase (eEF2 kinase), is activated in response to oxLDL, an effect that can be blocked by inhibiting calcium mobilization. Furthermore, selective inhibition of eEF2 kinase reverses the prosurvival effect of oxLDL and results in cellular apoptosis. p38 MAP kinase, a negative regulator of eEF2 kinase, is activated on growth factor withdrawal, a response that can be inhibited by oxLDL. Finally, we show that oxLDL, by activating eEF2 kinase, phosphorylates and therefore inhibits eEF2, resulting in an overall decrease in protein synthesis. These results indicate a novel signaling pathway in which oxLDL can block macrophage apoptosis by mobilizing calcium and activating eEF2 kinase.

Enhancing apolipoprotein A-I-dependent cholesterol efflux elevates cholesterol export from macrophages in vivo

Eight proteins potentially involved in cholesterol efflux [ABCA1, ABCG1, CYP27A1, phospholipid transfer protein (PLTP), scavenger receptor type BI (SR-BI), caveolin-1, cholesteryl ester transfer protein, and apolipoprotein A-I (apoA-I)] were overexpressed alone or in combination in RAW 264.7 macrophages. When apoA-I was used as an acceptor, overexpression of the combination of ABCA1, CYP27A1, PLTP, and SR-BI (Combination I) enhanced the efflux by 4.3-fold. It was established that the stimulation of efflux was due to increased abundance of ABCA1 and increased apoA-I binding to non-ABCA1 sites on macrophages. This combination caused only a small increase of the efflux to isolated HDL. When HDL was used as an acceptor, overexpression of caveolin-1 or a combination of caveolin-1 and SR-BI (Combination II) was the most active, doubling the efflux to HDL, without affecting the efflux to apoA-I. When tested in the in vivo mouse model of cholesterol efflux, overexpression of ABCA1 and Combination I elevated cholesterol export from macrophages to plasma, liver, and feces, whereas overexpression of caveolin-1 or Combination II did not have an effect. We conclude that pathways of cholesterol efflux using apoA-I as an acceptor make a predominant contribution to cholesterol export from macrophages in vivo.

Abstract 1952: ABCA1 Deficency Diminishes Dysfunctional HDL And Inhibits Early Atherosclerotic Lesion Development In SR-BI Knockout Mice

Objective: ABCA1 and SR-BI play an essential role in reverse cholesterol transport (RCT) from macrophages in the arterial wall to the liver. The aim of this study was to investigate the effect of combined total-body ABCA1 and SR-BI deficiency on lipoprotein metabolism and atherosclerosis. Methods &amp; Results: ABCA1/SR-BI double knockout (dKO), ABCA1 KO (AKO), SR-BI KO (SKO), and wildtype (WT) littermates were fed an atherogenic diet for 10 weeks to induce atherosclerosis. Under these conditions, SR-BI deficiency leads to largely increased serum cholesterol (C) levels (SKO: 470±68 mg/dL vs WT: 181±9 mg/dL, p&lt;0.001), due to an impaired removal of HDL-C and VLDL-C, while hampered HDL production in AKO mice resulted in cholesterol levels of only 23±4 mg/dL (p&lt;0.0001). In dKO mice, HDL-C was similarly low as in single AKO mice. Total serum cholesterol levels, however, were 3.8-fold (p&lt;0.001) higher, due to increased VLDL-C levels. Interestingly, more extreme foam cell accumulation was observed in the peritoneal cavity of dKO mice ((30±6%, p&lt;0.01), as compared to WT (1.7±0.2%), SKO (2.5±0.3%), and AKO (5±2%) mice. Combined deletion of ABCA1 and SR-BI thus induces macrophage foam cell formation in vivo . The accumulation of HDL-C and VLDL-C in SKO mice dramatically induced atherosclerotic lesion formation (206±16x10 3 μm 2 vs 12±2x10 3 μm 2 for WT mice, p&lt;0.001)), while lesions were only 33±12x10 3 μm 2 (p&lt;0.05) in AKO and 51±19x10 3 μm 2 (p&lt;0.01) in dKO mice with low HDL-C levels. Thus, despite enhanced foam cell formation in dKO mice, ABCA1 deletion reduces the atherosclerosis susceptibility of SKO mice. Next, the serum atherogenicity was tested by incubation of RAM cells with 3% serum of different types of mice. Serum from SKO mice induced more extreme foam cell formation (89±2%, p&lt;0.001), compared to serum from WT (31±3%), AKO (2.3±0.1%), and dKO (3.1±0.5%) mice. Interestingly, this effect highly correlated with both HDL-C (r=0.98, p&lt;0.0001) and VLDL/LDL-C levels (r=0.96, p&lt;0.0001). Conclusion: Total-body ABCA1 deficiency inhibits early atherosclerotic lesion development in SR-BI KO mice, which might be attributable to reduced circulating levels of pro-atherogenic HDL. Furthermore, both SR-BI and ABCA1 are essential for maintaining HDL-mediated RCT.

Abstract 5763: Dynamic Contrast-Enhanced MRI Detects Early Plaque Progression in a Rabbit Model of Atherosclerosis

Recent studies have used dynamic contrast-enhanced (DCE) MRI to quantify the rate of uptake of gadolinium contrast agents in atherosclerotic plaque. The transfer constant K trans , that quantifies the blood supply and permeability of the plaque, shows strong association with plaque inflammation. The purpose of this study was to explore the link between K trans and plaque inflammation in a model of early atherosclerotic lesion development. Twelve NZW rabbits were placed on a 0.2% cholesterol diet and underwent balloon injury of the descending aorta. After 12 weeks, all rabbits underwent a DCE-MRI exam, after which 6 were euthanized and perfusion fixed to harvest the atherosclerotic aortas. The remaining 6 were imaged again at 24 weeks and their aortas were harvested. The DCE-MRI procedure utilized a unique, high-speed, small field-of-view imaging technique with quadruple inversion recovery blood suppression (turbo spin echo, TR=800 ms, TE=9ms, 3mm slice thickness, 0.5mm in-plane resolution). This allowed us to observe enhancement of the vessel wall without contamination from enhancement of the adjacent lumen. The DCE-MRI results were analyzed to determine the average, relative K trans in the vessel wall and compared to histological assessments of the aortas. K trans was significantly higher at 6 months compared to 3 months within the same animals (p&lt;0.005) and compared to those euthanized at 3 months (p&lt;0.001). No difference was observed between the two groups at 3 months (p=0.4). Histologically, aorta cross sections at 6 months had lesions that were no thicker than those at 3 months (0.49 vs. 0.45mm, p=0.6), but complex lesion features including necrotic cores, intraplaque hemorrhage, neovessels, and deep clusters of macrophages were significantly more common at 6 months (82% vs. 18%, p&lt;0.001). The transformation of the lesions from simple to complex morphologies from 12 weeks to 24 coincided with a significant rise in K trans . We attribute this rise to the development of neovessels in response to pro-inflammatory stimuli. We conclude that K trans can be used to probe lesion characteristics and complexity in early atherosclerosis, with applications in early diagnosis and treatment monitoring. This research has received full or partial funding support from the American Heart Association, AHA Pacific/Mountain Affiliate (Alaska, Arizona, Colorado, Hawaii, Idaho, Montana, Oregon, Washington &amp; Wyoming).

Genetically Programmed Biases in Th1 and Th2 Immune Responses Modulate Atherogenesis

Atherosclerotic lesions contain T lymphocytes, which orchestrate adaptive immunity and regulate many innate immune pathways. This study examined the influence of Th1 and Th2 helper cell subsets on atherogenesis in two ApoE(-/-) mouse strains, C57BL/6 and BALB/c, which display opposite T-cell subset polarizations. ApoE(-/-) BL/6 mice showed predominant Th1-like immune responses on polyclonal stimulation of splenic CD4(+) T cells and had IgG2a antibodies to oxidized low-density lipoprotein (a disease-related antigen) whereas ApoE(-/-) BALB/c mice displayed predominant Th2 responses by CD4(+) T cells and an IgG1 isotype response toward oxidized low-density lipoprotein. ApoE(-/-) BL/6 and BALB/c mice consumed a high-cholesterol diet for 10, 16, and 24 weeks with equivalent cholesterolemic responses. The Th1-slanted BL/6 mice developed significantly more atherosclerosis in the aortic root and abdominal aorta at all time points compared with BALB/c mice, supporting a proatherogenic role for Th1 response. Progression of atherosclerosis was associated with increased levels of interleukin (IL)-6 in mouse serum and CD4(+) T-cell culture supernatants and increased levels of the acute-phase protein, serum amyloid A (SAA). Both IL-6 and SAA levels rose significantly in ApoE(-/-) BL/6 mice compared with BALB/c mice. The circulating cytokine milieu (IL-6) and acute phase reactants such as SAA may reflect alterations in the Th1/Th2 balance. The results presented here illustrate how genetically determined modifiers of both immune and inflammatory responses can modulate atherogenesis independently of lipid levels.

HDL particles from type 1 diabetic patients are unable to reverse the inhibitory effect of oxidised LDL on endothelium-dependent vasorelaxation

In healthy individuals, HDL can counteract the inhibition of vasorelaxation induced by oxidised LDL. Several abnormalities such as increased size, glycation and decreased paraoxonase activity have been reported for HDL from type 1 diabetic patients. Thus, we hypothesised that the ability of HDL to protect vessels against impairments of vasorelaxation would be decreased in these patients. We compared the ability of HDL from 18 type 1 diabetic patients and 12 control participants to counteract the inhibition of endothelium-dependent relaxation induced by oxidised LDL on rabbit aorta rings. Serum triacylglycerol and total cholesterol, LDL- and HDL-cholesterol were similar in type 1 diabetic and control participants. Fasting glycaemia and the HDL-fructosamine level were higher in diabetic patients than in controls (9.06 +/- 3.55 vs 5.27 +/- 0.23 mmol/l, p < 0.005; and 10.2 +/- 3.2 vs 7.7 +/- 2.5 micromol/g protein, p < 0.05, respectively). HDL composition, size and paraoxonase activity were similar in both groups. HDL from controls reduced the inhibitory effect of oxidised LDL on maximal relaxation (E (max); 79.3 +/- 11.8 vs 66.4 +/- 11.7%, p < 0.05), whereas HDL from type 1 diabetic patients had no effect (E (max) = 70.6 +/- 17.4 vs 63.9 +/- 17.2%, NS). In type 1 diabetic patients, E (max) was not correlated with glycaemia or the HDL-fructosamine level. HDL particles from type 1 diabetic patients do not protect against inhibition of endothelium-dependent vasorelaxation induced by oxidised LDL, in contrast to HDL particles from healthy individuals. This defect cannot be explained by abnormalities in HDL composition, size or paraoxonase activity, and may contribute to the early development of atherosclerotic lesions in type 1 diabetic patients.

Total Body ABCG1 Expression Protects Against Early Atherosclerotic Lesion Development in Mice

ABCG1 has recently been identified as a facilitator of cholesterol and phospholipid efflux from macrophages to HDL. In bone marrow transplantation studies, we and others have now shown that the absence of macrophage ABCG1 may differentially influence atherosclerotic lesions dependent on the experimental setting and/or the stage of atherosclerotic lesion development. To further define the role of ABCG1 in atherogenesis, we investigated in the current study the effect of total body deficiency of ABCG1 on atherosclerotic lesion development. ABCG1-/- mice and wild-type littermates were fed an atherogenic diet for 12 weeks to induce atherosclerotic lesion formation. Both before and after the start of the atherogenic diet, serum lipid levels and lipoprotein profiles did not differ significantly between the two groups. In addition no significant difference in serum apoE levels was found after diet feeding. In wild-type mice the atherogenic diet induced the formation of macrophage-rich early lesions (size: 24+/-7x10(3) microm2 [n=6]). Feeding ABCG1-/- mice the atherogenic diet led to a significant 1.9-fold stimulation of atherosclerotic lesion size (46+/-6x10(3) microm2 [n=7]; Student t test P=0.034 and Mann-Whitney test P=0.050) compared with controls, suggesting a clear antiatherogenic role for ABCG1. At the same time, excessive lipid accumulation was observed in macrophage-rich areas of the lungs and spleens of ABCG1-/- mice as compared with wild-type mice. Total body ABCG1 expression protects against early atherosclerotic lesion development.

Increased leukotriene concentrations in gingival crevicular fluid from subjects with periodontal disease and atherosclerosis

Recent studies indicate that periodontal disease is associated with the development of early atherosclerotic lesions in the carotid artery. Since inflammation is a key feature in both atherosclerosis and periodontal disease, a common mediator of the two diseases could be anticipated. Leukotrienes are lipid-derived inflammatory mediators recently implicated in the pathogenesis of atherosclerosis and previously shown to be produced in periodontitis. The aim of the present study was to detect leukotrienes in gingival crevicular fluid (GCF) from subjects with atherosclerosis. Carotid ultrasonography and oral clinical examination were performed in 19 periodontitis patients and 16 healthy subjects. Atherosclerotic plaques were detected on ultrasound examination in 13 subjects with periodontits, and in 5 of the healthy subjects. Elevated concentrations of leukotriene B 4 and cysteinyl-leukotrienes were detected in GCF from subjects with a high dental plaque index (PLI > 0.3), supporting an increased leukotriene formation in periodontitis. In addition, subjects with atherosclerotic plaques had significantly elevated concentrations of cysteinyl-leukotrienes in their GCF as compared with subjects without a visible plaque. Finally, the increased cysteinyl-leukotriene concentrations in GCF from atherosclerotic subjects were observed also when sub groups of periodontis patients and healthy subjects were compared separately. In summary, increased GCF concentrations of cysteinyl-leukotrienes were correlated to measures of both periodontitis and atherosclerosis. These results suggest that increased leukotriene formation may represent a possible link between periodontitis and atherosclerosis and a risk factor marker for both diseases.

HIV protease inhibitors activate the unfolded protein response and promote foam cell formation in macrophages

Numerous clinic studies have suggested that HIV protease inhibitors (PIs) are closely linked to atherosclerotic cardiovascular disease. However, the exact mechanisms underling the HIV PI-induced atherosclerosis are still unclear. Macrophages play essential roles in both early atherosclerotic lesion development and late lesion complications. Our previous studies demonstrated that HIV PI (ritonavir) activated the unfolded protein response (UPR), significantly increased apoptosis, and promoted foam cell formation in macrophages. The current study further examines whether all of the HIV PIs have the similar effects on the UPR activation, inflammatory cytokine release, and foam cell formation. Methods Mouse J774A.1 cells were used in this study. Expression of the UPR responsive genes, including CHOP, ATF-4 and XBP-1 were detected by Western Blot analysis. TNF-α and IL-6 levels in the media were determined by enzyme-linked immunosorbent assay. Intracellular lipids were detected with Oil Red O staining. Results All HIV PIs, except amprenavir, activated the UPR, induced TNF-α and IL-6 release, and promoted foam cell formation to varying degrees. Conclusions These results suggest that HIV PIs differ greatly in their ability to activate the UPR, increase inflammatory cytokine release and promote foam cell formation in macrophages. These results provide critical information for a better understanding of the cellular mechanisms of HIV PI-associated atherosclerosis and developing new therapeutic strategies to avoid some of the adverse side effects caused by current HIV PIs. This work is supported by grants from the National Institutes of Health (R01 AI057189, P01 DK38030), GlaxoSmithKline research fund and A.D. Williams fund.

W12-P-088 Immune inflammation and development of early atherosclerotic lesions in the aorta and pulmonary artery

W12-P-088 Immune inflammation and development of early atherosclerotic lesions in the aorta and pulmonary artery

Alteration in fluid mechanics in porcine femoral arteries with atheroma development.

Although the relationship between the local wall shear stresses (WSS) and atheroma development has been previously studied, the effect of variable regional wall distensibility with early atherosclerotic lesions and its effect on local hemodynamics have not been well investigated. We induced early atherosclerotic lesion development in one femoral artery in a Yucatan miniswine model with the contralateral artery serving as control. Eight weeks following atheroma formation, hemodynamic and intravascular ultrasound image data were obtained. Using the measured regional arterial distension as the moving boundary condition, unsteady laminar incompressible computational analysis was performed on the reconstructed arterial segments. With the development of early atherosclerotic lesions, there was increased wall distensibility and an increase in the computed normalized wall shear stress amplitude (NWSA). Alterations in the local fluid mechanics and mass transport at these sites may need to be considered in our understanding of the continued growth of these lesions.

Exclusive expression of transmembrane TNF-α in mice reduces the inflammatory response in early lipid lesions of aortic sinus

We investigated the effect of transmembrane form of tumor necrosis factor-alpha (TNF) on atherosclerosis in mice. We compared the development of early atherosclerotic lesions in the aortic sinus of (1) TNF-deficient mice that express only a non-cleavable transmembrane form of TNF (tmTNF), (2) wild-type (WT) C57BL/6 mice, and (3) TNF-deficient mice (TNF −/−). All mice were fed an atherogenic diet for 20 weeks. Lipid deposition was the most prominent in WT mice (25030±5693 μm 2), tended to be lower in tmTNF mice (13640±2190 μm 2, P>0.05 versus WT mice) and rare in TNF −/− mice (1408±513 μm 2, P<0.05 versus tmTNF and P<0.01 versus WT). Macrophage accumulation was five-fold lower ( P<0.01) in tmTNF than in WT mice. In addition, the α-actin immuno-reactivity of medial smooth muscle cells remained intact in tmTNF mice but not in WT mice. In WT mice, the plasma lipid profile was significantly more atherogenic than that of TNF −/− mice ( P<0.05), but not significantly different from that of tmTNF mice ( P>0.05). These results indicated that in contrast to TNF −/− mice, mice expressing exclusively tmTNF were not completely protected from early atherosclerotic lesion formation, although their lesions have a less inflammatory state than those of WT mice, which underlines the stronger proinflammatory potential of soluble TNF.

Molecular mechanisms mediating inflammation in vascular disease: special reference to monocyte chemoattractant protein-1.

There are several clinical challenges for the treatment of intractable cardiovascular diseases, including restenosis, atherosclerotic complications resulting from plaque rupture, severe tissue ischemia, and heart failure. Emerging evidence suggests that an inflammatory process is involved in the pathogenesis of such intractable diseases. In particular, inflammatory responses to arterial injury, which cause continuous recruitment and activation of monocytes mainly through activation of the monocyte chemoattractant protein-1 (MCP-1) pathway, have a central role in restenosis and atherogenesis. We recently devised a new strategy for anti-MCP-1 therapy by transfecting an N-terminal deletion mutant of the MCP-1 gene into skeletal muscles. This mutant MCP-1 lacks the N-terminal amino acids 2 to 8, called 7ND, and works as a dominant-negative inhibitor of MCP-1. We demonstrated that 7ND gene transfer suppresses monocyte infiltration/activation after arterial injury and markedly inhibits experimental restenosis in animals after balloon injury or stent placement. Furthermore, 7ND gene transfer not only attenuated the development of early atherosclerotic lesions but also limited progression of preexisting atherosclerotic lesions and changed the lesion composition into a more stable phenotype in hypercholesterolemic mice. Vascular inflammation mediated by MCP-1 might create a positive feedback loop to enhance restenotic and atherosclerotic changes through activating lesional monocytes. Therefore, vascular inflammation mediated by MCP-1 has a central role in the development of experimental restenosis, atherosclerosis, and plaque destabilization, leading to acute coronary syndrome. This strategy for gene therapy might be useful against human restenosis, thereby opening a new therapeutic window for antirestenosis and antiatherosclerosis paradigms.