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John T Fallon

Publications and source records attributed to John T Fallon.

At least 37 records · Page 2Linked to original sources
PubMed2003

Chemokine receptor-8 (CCR8) mediates human vascular smooth muscle cell chemotaxis and metalloproteinase-2 secretion.

The response of the arterial vascular wall to injury is characterized by vascular smooth muscle cell (VSMC) migration, a process requiring metalloproteinase production. This migration is induced by cytokines, however the agonists involved are not fully defined. The CC chemokine receptor 8 (CCR8) is expressed on monocytes and T lymphocytes and is the sole receptor for the human CC chemokine 1 (CCL1, I-309) and for the viral chemokine, vCCL1 (viral macrophage inflammatory protein 1 [vMIP-1]). We have reported that CCR8 is expressed on human umbilical vein endothelial cells (HUVECs) and mediates chemotaxis induced by CCL1. The conditioned medium from incubation mixtures of lipoprotein(a) (Lp(a)) and HUVECs (LCM) contained CCL1 and stimulated both monocyte and HUVEC chemotaxis, providing novel mechanisms for the atherogenicity of Lp(a). We now report that CCL1, vCCL1, and LCM stimulate chemotaxis of human VSMCs that is blocked by murine monoclonal antibody against CCR8 and by the G-protein inhibitor pertussis toxin. The effect of anti-CCR8 was specific, as this antibody failed to effect the chemotaxis of VSMCs in response to CCL3 or by platelet-derived growth factor BB (PDGF-BB). VSMCs contained CCR8 mRNA and CCR8 antigen coprecipitated with VSMC membranes. Antibodies against metalloproteinase-2 (MMP-2) inhibited the CCL1-induced chemotaxis of VSMCs, whereas anti-MMP-9 was less effective. CCL1 induced VSMC pro-MMP-2 mRNA and protein secretion. Poxvirus MC148 inhibited the increase in MMP-2 induced by CCL1, documenting that CCR8 was the receptor responsible. In mouse femoral arteries, CCR8 and TCA3 antigen colocalized with VSMCs and were up-regulated after injury. The induction of CCR8 and CCL1/TCA3 under conditions associated with VSMC proliferation and migration raises the possibility that CCR8 may play an important role in vessel wall pathology.

Amino Acid Sequence↗
PubMed2003

The p17 cleaved form of caspase-3 is present within viable macrophages in vitro and in atherosclerotic plaque.

OBJECTIVE: In vitro studies of macrophage death in response to oxidized LDL (oxLDL) were undertaken as a model for the formation of the necrotic core of atherosclerotic plaque. METHODS AND RESULTS: Thioglycollate-elicited mouse peritoneal macrophages avidly incorporated both oxLDL and acetylated LDL (acLDL) to become foam cells. oxLDL-treated macrophages, but not acLDL-treated macrophages, showed nearly 100% death, with characteristics consistent with apoptosis, including cell surface phosphatidylserine exposure, intracellular caspase-3 activity, cleavage of caspase-3 substrates, and DNA fragmentation, as shown by TUNEL assay. The activated form of caspase-3 (p17 cleaved form) was present in attached, viable macrophages before exposure to oxLDL. This p17 form was also found in apparently viable as well as in TUNEL-positive cells within atherosclerotic lesions of chow-fed apolipoprotein E-deficient (ApoE-/-) mice. The amount of p17 caspase-3 was reduced by in vitro blockade of FasL with an FasL-blocking antibody and was absent in macrophages from lpr/lpr mice, which lack functional Fas. Moreover, lpr/lpr macrophages resisted oxLDL cytotoxicity. CONCLUSIONS: The naturally occurring Fas-FasL induction of caspase-3 cleavage after macrophage attachment may represent an important physiologic mechanism that primes for cytotoxicity by oxLDL and possibly, other death-inducing molecules.

Amino Acid Chloromethyl Ketones↗
PubMed2003

Decreased reendothelialization and increased neointima formation with endostatin overexpression in a mouse model of arterial injury.

BACKGROUND: Impaired endothelial regeneration contributes to arterial lesion formation. Endostatin is a specific inhibitor of endothelial cell growth and induces endothelial cell apoptosis. We examined the effect of endostatin overexpression on reendothelialization and neointima formation in a mouse model of arterial injury. METHODS AND RESULTS: Mice underwent femoral arterial denudation and received recombinant adenovirus, expressing either murine endostatin (n=19) or control adenoviral vector (n=12), by jugular vein injection. Endostatin gene transfer resulted in high serum levels of endostatin. Strong adenoviral gene expression of beta-galactosidase-expressing control vector was detected in liver tissue and was absent in the injured arterial wall at 1 week. Deposits of endostatin protein were detected along the denuded arterial wall and were not seen in the noninjured contralateral artery at 1 week. Endostatin deposits were also absent in the injured artery of control vector-treated animals. Overexpression of endostatin led to decreased reendothelialization and increased apoptosis of luminal endothelial cells 2 and 4 weeks after arterial injury (P<0.05). In addition, endostatin overexpression resulted in increased neointima formation (P<0.05). Endothelial apoptosis and neointima area correlated positively with endostatin serum levels, whereas the degree of reendothelialization correlated negatively with endostatin serum levels (P<0.05). Furthermore, poor reendothelialization correlated with increased neointima formation (P<0.05). CONCLUSIONS: In summary, decreased reendothelialization and enhanced endothelial apoptosis, in response to endostatin overexpression, were associated with increased neointima formation. These findings demonstrate that high serum levels of endostatin are capable of inhibiting endothelial regeneration and promoting arterial lesion growth in conditions of endothelial injury.

Adenoviridae↗
PubMed2003

A novel nonobstructive intravascular MRI coil: in vivo imaging of experimental atherosclerosis.

OBJECTIVE: MRI is being used to characterize the composition of atherosclerotic plaques. However, the resolution achievable using surface radiofrequency coils is limited by the signal to noise ratio. We studied the utility of a new intravascular (IV) MRI probe for high-resolution in vivo imaging of atherosclerotic lesions. METHODS AND RESULTS: Balloon-injured Watanabe heritable hyperlipidemic rabbits served as the experimental model of atherosclerosis. The newly developed IV MRI probe is 1.3 mm in diameter and can be positioned over a guidewire. MRI was performed with both an external phased-array coil and the IV MR coil. MR observations were correlated with histopathology. After MRI, the animals were killed and analysis of agreement between MR and histopathology was performed. The IV MR coil allows aortic images to be obtained with 156x156 micro m(2) in-plane resolution versus 352x352 micro m(2) when used with the external phased-array coil. No significant motion artifacts were noted, despite the continuation of arterial blood flow during image acquisition around the IV probe. The different components of the atherosclerotic lesions (lipid core and fibrous cap) were easily identified. There was an excellent agreement between MRI with the IV coil and histopathology by simple linear regression for both the mean wall thickness (r=0.88, slope 0.82, P<0.0001) and vessel wall area (r=0.86, slope 1.08, P<0.0001). CONCLUSIONS: The new nonobstructive design for this intravascular coil provides great promise for additional work in high-resolution MRI characterization of atherosclerotic plaques in vivo. The ability to position the probe with a guidewire allows its placement under fluoroscopic or MRI guidance, whereas its size is compatible with human coronary arteries.

Animals↗
PubMed2003

Serial, noninvasive, in vivo magnetic resonance microscopy detects the development of atherosclerosis in apolipoprotein E-deficient mice and its progression by arterial wall remodeling.

PURPOSE: To test the ability of serial, in vivo magnetic resonance microscopy (MRM) to detect the development of atherosclerosis and quantify its progression in apolipoprotein E-deficient mice. MATERIALS AND METHODS: The abdominal aortae of six ApoE(-/-) and three wild-type (WT) control mice were imaged by MRM at 9.4T. Proton density weighted images were obtained (TR = 2000, TE = 9 msec) using four signal averages. The image resolution was 109 x 109 x 500 microm(3). The six ApoE(-/-) mice underwent serial MRM three to five times over a period < or = 44 weeks. Multiple, anatomically aligned MRM slices (N = 6-11 per time point, total 202) were compared serially in each animal. RESULTS: The abdominal aorta remained free of atherosclerosis until 20 weeks of age but thereafter, atherosclerosis was identified in all ApoE(-/-) mice (P < 0.05 to P < 0.001), but no WT controls. Lesion progression was accompanied by positive remodeling in which atherosclerosis within the aortic wall was accommodated by an increase in total cross sectional area (P < 0.01), while lumen area was unchanged. CONCLUSION: Serial MRM demonstrated the development and progression of atherosclerosis in mouse aorta. Importantly, progression of atherosclerosis could be identified within individual animals. By following the same aortic lesions over time, MRM demonstrated that progression of atherosclerosis in mice is associated with positive arterial remodeling.

Animals↗
PubMed2003

Dietary glycotoxins promote diabetic atherosclerosis in apolipoprotein E-deficient mice.

Hyperglycemia derived advanced glycation endproducts (AGE) have been implicated in diabetic atherosclerosis (AS) but the role of exogenous (dietary) AGE in the development of this serious complication is not known. This study evaluates the influence of diet-related AGE on AS in genetically hypercholesterolemic apolipoprotein E-deficient (apoE(-/-)), streptozotocin-induced diabetic mice. Diabetic and non-diabetic apoE(-/-) mice (6-8 weeks old) were randomized into either a standard AIN-93G chow (AGE 12,500+/-700 U/mg, termed high-AGE diet, H-AGE), or the same chow having four to fivefold lower AGE level (L-AGE: 2,700+/-830 U/mg) based on ELISA. After 2 months of diabetes, compared to the diabetic mice fed standard (H-AGE) diet, the AS lesions at the aortic root of the L-AGE group were >50% smaller (0.17+/-0.03 vs. 0.31+/-0.05 mm(2), P<0.05). Serum AGE were lower in the diabetic L-AGE than in the H-AGE mice (by approximately 53%) (P<0.00001), as were in the non-diabetic L-AGE vs. H-AGE groups (P<0.05). No diet-related changes were noted in plasma glucose, triglycerides, or plasma cholesterol. Immunohistochemical comparisons showed markedly suppressed tissue AGE, AGE-Receptor-1, -2 and RAGE expression, reduced numbers of inflammatory cells, tissue factor, vascular cell adhesion molecule-1 and MCP-1 in the L-AGE diabetic group. The findings are supportive of an important link between dietary intake of pre-formed glycoxidation products, tissue-incorporated AGE, and diabetes-accelerated AS. The marked anti-atherogenic effects of an AGE-restricted diet in this model may provide the basis for relevant clinical studies.

Animals↗
PubMed2003

Refractory pulmonary hypertension in a lupus patient with occult pulmonary vasculitis.

Primary pulmonary hypertension is a disease that has become increasingly recognized in lupus patients. Pathologic findings from lupus patients usually do not differ from those who have idiopathic pulmonary hypertension. In recent years, intravenous vasodilator therapy has improved morbidity and mortality in patients with primary pulmonary hypertension. In this case report, we describe a young woman with severe pulmonary hypertension refractory to aggressive parenteral vasodilator treatment. Steroid treatment was initiated after a tentative diagnosis of lupus was made on the basis of the presence of Raynaud's phenomenon, proteinuria, pericarditis with tamponade, and a positive anti-Ro antibody. Despite treatment with vasodilators and steroids, the patient's condition rapidly deteriorated and she died. Unexpectedly, active pulmonary arteritis was demonstrated at autopsy. This case suggests that immunosuppressive therapy should be considered in lupus patients with severe pulmonary hypertension who are refractory to aggressive vasodilator therapy and high-dose parenteral steroids.

Journal Article↗
PubMed2003

Endovascular aortic biopsy in the diagnosis of takayasu arteritis.

PURPOSE: To use a minimally invasive approach to obtain biopsy specimens of the aorta to confirm the diagnosis of Takayasu arteritis and formulate a therapeutic plan. CASE REPORT: A 17-year-old woman with lower extremity claudication and a normal erythrocyte sedimentation rate had magnetic resonance angiography, which suggested stenotic lesions of the infrarenal aorta and left renal artery. An endovascular biopsy of the aortic lesion was performed under local anesthesia, retrieving sufficient tissue to make the diagnosis of Takayasu arteritis. The patient was discharged the same day. CONCLUSIONS: Endovascular aortic biopsy may be useful in diagnosing Takayasu arteritis and guiding the clinician toward the proper mode of treatment.

Adolescent↗
PubMed2002

Remodeling of small intramyocardial coronary arteries distal to a severe epicardial coronary artery stenosis.

OBJECTIVE: Impaired coronary blood flow (CF) or flow reserve with incomplete and delayed recovery of left ventricular (LV) function after revascularization is common in severe ischemic LV dysfunction. The underlying mechanism is not fully known. We studied structural changes of small intramyocardial coronary arteries (SIMCAs) in a pig model of chronic coronary stenosis, testing the hypothesis that microvascular remodeling develops distally to a severe epicardial coronary artery stenosis. METHODS AND RESULTS: A total of 24 pigs were studied in 3 groups. Left anterior descending coronary stenosis was created to reduce CF by a mean of approximately 30%, producing severe regional systolic dysfunction without infarction. The stenosis was maintained for 7 days in 6 pigs (Group 1) and for 4 weeks in 12 pigs (Group 2). The control group (Group 3) consisted of 6 pigs with the same surgical procedures but without stenosis. The wall thickness (WTa) and lumen (L) diameter of SIMCA were measured, and the ratio of WTa/L and lumen area/total vessel area (% lumen) were calculated. The composition of the arterial wall was studied with cell proliferation markers Ki67 and BrdU. The immediate reduction in CF after the creation of the stenosis was similar in both study groups, but after the first week, CF decreased significantly (P<0.05) when the stenosis was maintained (group 2). The left anterior descending stenosis caused regional LV dysfunction in all pigs (groups 1 and 2). After 4 weeks of stenosis with chronic myocardial hibernation (group 2), but not after 1 week (group 1), WTa and WTa/L increased and L decreased significantly in the chronic hibernating region located distally to the stenosis, compared with both the control (group 3) and the normal region in the same pig. The mean % lumen of SIMCA per pig correlated with the CF reduction (r=0.92, P<0.001) and with myocardial fibrosis (r=0.82, P<0.01) in the 4-week stenosis group. Ki67- and BrdU-positive cells were increased in the wall of SIMCA in Group 1 and 2 compared with the control group (P<0.01 for each). The proliferated cells were stained positively with smooth muscle alpha-actin antibody. CONCLUSION: In the chronic ischemic, hibernating myocardial region distal to a flow-limiting epicardial coronary stenosis, the small intramyocardial coronary arteries undergo remodeling, with an increase in wall thickness and a decrease in lumen. These structural changes may further restrict blood flow to ischemic myocardium and may account for the pathophysiologic impairment of CF or flow reserve after revascularization, which leads to delayed or incomplete recovery of myocardial function.

Animals↗
PubMed2002

Tacrolimus in cardiac transplantation: efficacy and safety of a novel dosing protocol.

BACKGROUND: Although used for more than 20 years, optimal dosing strategies of most immunosuppressants have never been determined. Tacrolimus, one of the newer agents used in solid-organ transplantation, is gaining increasing popularity because of its ability to reverse refractory rejection in cyclosporine-treated patients and its favorable side-effect profile. As with many other immunosuppressive agents, absorption and metabolism vary between individuals, which complicates dosing. METHODS: We hypothesized that a 1-mg dose of tacrolimus may be used to gauge each patient's metabolism. A novel dosing scheme was evaluated to establish the safety and efficacy of this approach. Outcomes were incidence of renal insufficiency and treatment efficacy as assessed by the rejection grade on the first endomyocardial biopsy. RESULTS: The risk of renal insufficiency was low, with only a 3% rise in creatinine at 7 days posttransplant. The risk of renal insufficiency was highest during the first 3 days of tacrolimus therapy, and the change in tacrolimus level during this time was identified as the single best predictor of renal insufficiency. From days 4 to 7, the rise in tacrolimus level had much less influence on renal function. Ninety-two percent of patients had a low- or intermediate-grade first cardiac biopsy. CONCLUSIONS: It was shown that this conservative initial dosing approach, which guarantees renal safety, is not associated with an increased risk of allograft rejection. We conclude that administration of tacrolimus via a tailored protocol soon after transplantation ensures a safe and effective means of immunosuppression.

Adult↗
PubMed2002

Effects of abciximab on the acute pathology of blood vessels after arterial stenting in nonhuman primates.

OBJECTIVES: This study was designed to assess the effect of abciximab on platelet and leukocyte deposition 60 min after stent insertion in nonhuman primates. BACKGROUND: Although it is well established that abciximab improves both short- and long-term clinical outcomes after stent placement, there have been no studies assessing its effect on early platelet and leukocyte deposition. METHODS: Cynomolgus monkeys were pretreated with aspirin and either saline or a 0.4 mg/kg bolus of abciximab, and then subjected to angioplasty and Palmaz-Schatz stent placement in the common iliac artery or abdominal aorta. After 60 min, animals were euthanized and the stented artery was evaluated by immunohistochemistry and morphometry. RESULTS: Complete occlusion of the stented vessel with a thin fibrin(ogen) meshwork and trapped blood occurred in two saline-treated and two abciximab-treated animals. In the four remaining saline-treated animals, a layer of erythrocytes trapped in a network of fibrin(ogen) was noted close to the vessel wall, and this was covered by a layer of large, irregular platelet thrombi. Leukocytes formed a monolayer on top of the platelets and near stent struts. In the four remaining abciximab-treated animals, the mean erythrocyte area was 65% smaller (p = 0.070), the platelet aggregate area was 89% smaller (p = 0.049) and the luminal area was 59% larger (p = 0.004). A monolayer of leukocytes also formed on top of the platelets and near stent struts. CONCLUSIONS: In control stented blood vessels in this study, platelet thrombi formed not at the vessel wall, but on top of an erythrocyte-rich layer, and platelets recruited leukocytes. Abciximab decreased the size of platelet thrombi, but did not prevent leukocyte recruitment.

Abciximab↗
PubMed2002

In vivo noninvasive detection and age definition of arterial thrombus by MRI.

OBJECTIVES: The purpose of this study was to evaluate the potential of magnetic resonance (MR) to detect arterial thrombotic obstruction and define thrombus age. BACKGROUND; Arterial thrombi underlie the clinical consequences of atherosclerosis and are not reliably detected by current noninvasive diagnostic techniques. METHODS: Carotid thrombi were induced in swine (n = 7) by arterial injury. Serial high-resolution in vivo MR images were obtained using black-blood T1-weighted (T1W) and T2-weighted (T2W) sequences in a clinical 1.5T MR system at 6 h, 1 day and at 1, 2, 3, 6 and 9 weeks. At each time point one animal was sacrificed and the occluded carotid artery processed for histopathology. Thrombus signal intensity (SI) was normalized to that of the adjacent muscle. Thrombus age was assessed based on MR appearance by two blinded independent observers. RESULTS: Thrombus appearance and relative SI revealed characteristic temporal changes in multicontrast-weighted MR images, reflecting histologic changes in the composition. Acute thrombus appeared very bright on the T2W images, facilitating the detection. Signal intensity was 197 +/- 25% at 6 h, peaking at 1 week (246 +/- 51%), reaching a plateau by 6 weeks (120 +/- 15%). At six weeks, complete thrombus organization was confirmed histologically. The T1W images had similar pattern with lower SI than T2W. Age definition using visual appearance was highly accurate (Pearson's chi-square with 4 df ranging from 96 to 132 and Cohen's kappa at 0.81 to 0.94). Agreement between observers was substantial (Pearson chi-square with 4 df = 91.5, kappa = 0.79). CONCLUSIONS: Magnetic resonance imaging is a promising tool to noninvasively detect arterial thrombosis. Measurement of SI and the characteristic visual appearance of the thrombus have the potential to define thrombus age.

Age Factors↗
PubMed2002

CCR2 deficiency decreases intimal hyperplasia after arterial injury.

Monocyte chemoattractant protein (MCP)-1 is upregulated in atherosclerotic plaques and in the media and intima of injured arteries. CC chemokine receptor 2 (CCR2) is the only known functional receptor for MCP-1. Mice deficient in MCP-1 or CCR2 have marked reductions in atherosclerosis. This study examines the effect of CCR2 deficiency in a murine model of femoral arterial injury. Four weeks after injury, arteries from CCR2(-/-) mice showed a 61.4% reduction (P<0.01) in intimal area and a 62% reduction (P<0.05) in intima/media ratio when compared with CCR2(+/+) littermates. The response of CCR2(+/-) mice was not significantly different from that of CCR2(+/+) mice. Five days after injury, the medial proliferation index, determined by bromodeoxyuridine incorporation, was decreased by 59.8% in CCR2(-/-) mice when compared with CCR2(+/+) littermates (P<0.05). Although leukocytes rapidly adhered to the injured arterial surface, there was no significant macrophage infiltration in the arterial wall of either CCR2(-/-) or CCR2(+/+) mice 5 and 28 days after injury. These results demonstrate that CCR2 plays an important role in mediating smooth muscle cell proliferation and intimal hyperplasia in a non-hyperlipidemic model of acute arterial injury. CCR2 may thus be an important target for inhibiting the response to acute arterial injury.

Animals↗
PubMed2002

Progression and regression of atherosclerotic lesions: monitoring with serial noninvasive magnetic resonance imaging.

BACKGROUND: Modification or stabilization of atherosclerotic plaques has been proposed as the mechanism responsible for the beneficial clinical effect of lipid-lowering therapies. An imaging modality able to quantify atherosclerotic plaque composition could potentially allow not only the identification of these vulnerable atherosclerotic lesions, but also monitoring of the effects of therapeutic interventions on plaque composition. Our aim was to monitor changes in burden and composition of atherosclerotic plaques in a rabbit model of complex atherosclerosis using serial noninvasive magnetic resonance imaging (MRI). METHODS AND RESULTS: Aortic atherosclerotic lesions were induced in rabbits and the animals randomized to continue an atherogenic diet (atherosclerosis progression) or resume normal chow (atherosclerosis regression) for 6 months. MRI of the aorta was performed at 3 time points in each rabbit, as follows: baseline, after atherosclerosis induction (9 months old), and after atherosclerosis regression or progression (15 months old). Histopathologic correlation with MRI was performed. There was a significant (P<0.0001) reduction in atherosclerotic burden in the regression group, and an increase in the progression group. There was a significant (P<0.001) reduction in the lipidic component of plaques in the regression group, and an increase in the progression group. A small, nonsignificant increase in the fibrotic plaque components was noted in the regression group, but a significant decrease in the fibrotic composition of lesions in the progression group. A significant correlation (P<0.001) was found between MRI and histopathology for atherosclerotic burden and plaque composition. CONCLUSIONS: These findings indicate that serial noninvasive MRI can monitor changes in atherosclerotic plaque composition under conditions of atherosclerotic progression and regression.

Aging↗
PubMed2002

Atherosclerotic lesions in genetically modified mice quantified in vivo by non-invasive high-resolution magnetic resonance microscopy.

We have previously shown that magnetic resonance microscopy (MRM) accurately quantifies atherosclerosis in Apolipoprotein E deficient (ApoE(-/-)) mice aged 36-84 weeks. The present study tests MRM in the quantification of aortic atherosclerosis over a broader range of lesion severity. Younger mice with less advanced disease were imaged in order to evaluate sensitivity, specificity and maximum practical resolution of MRM. Nineteen mice underwent in vivo MRM. Wall area measurements by MRM and light microscopy (LM) (n=43) were highly correlated (r=0.85, slope=0.88, P<0.0001). Wall areas by MRM ranged from 0.114 to 0.934 (median, 0.334) mm(2). A threshold of 0.35 mm(2), for the upper limit of normal, gave MRM positive predictive value (PPV) for detecting abnormally thickened arteries=89.5% and negative predictive value (NPV)=75%, referred to LM. Lesion shape assessed by LM and MRM were also well correlated (r=0.72, P<0.001). Increased wall area in atherosclerosis was found by MRM (P=0.01) and LM (P<0.0001) to be accommodated entirely by 'positive remodeling', confirming the importance of determining plaque size directly. MRM accurately quantifies mouse aortic atherosclerosis and will enhance studies in this important animal model.

Animals↗
PubMed2002

Lowering of dietary advanced glycation endproducts (AGE) reduces neointimal formation after arterial injury in genetically hypercholesterolemic mice.

Restenosis remains a major cause of morbidity and mortality after coronary angioplasty. Injury-induced inflammation, thrombosis, smooth muscle cell (SMC) proliferation, and neointimal formation contribute to restenosis. These events are linked to circulating glucose-derived advanced gycation endproducts (AGE), known to promote cell proliferation, lipid glycoxidation and oxidant stress. This study evaluates the association between dietary AGE content and neointimal formation after arterial injury in genetically hypercholesterolemic mice. Male, 12-week-old, apolipoprotein E-deficient (apoE(-/-)) mice were randomly assigned to receive either a high AGE diet (HAD; AGE=15000 U/mg), or a similar diet with ten-fold lower AGE (LAD; AGE=1500 U/mg). These mice underwent femoral artery injury 1 week later, and were maintained on their diets for an additional 4 weeks. At 4 weeks after injury, significant decrease in neointimal formation was noted in LAD-fed mice. Neointimal area, intima/media ratio, and stenotic luminal area (LA) were less pronounced in the LAD group than the HAD group (P<0.05). These quantitative differences were associated with a marked reduction ( approximately 56%) of macrophages in the neointimal lesions, as well as an obvious reduction of SMC content of LAD-fed mice. The reduction of neointimal formation in the LAD mice correlated with a approximately 40% decrease in circulating AGE levels (P<0.0005). Immunohistochemistry also showed a reduced ( approximately 1.5-fold) deposition of AGE in the endothelia, SMC, and macrophages in neointimal lesions of LAD-fed mice. These results represent the first evidence in vivo for a causal relationship between dietary AGE and the vessel wall response to acute injury, suggesting a significant potential for dietary AGE restriction in the prevention of restenosis after angioplasty.

Animals↗
PubMed2002

Hepatocyte growth factor is a survival factor for endothelial cells and is expressed in human atherosclerotic plaques.

Hepatocyte growth factor (HGF) has multiple effects on target cells upon activation of its receptor, c-Met. In endothelial cells, HGF induces migration, proliferation, and angiogenesis. HGF can also act as an anti-apoptotic factor for several cell types. The signal transduction pathways involved in mediating its anti-apoptotic effects have not been fully clarified. We demonstrated that HGF is anti-apoptotic for human endothelial cells, and identified the signaling pathways by which it mediates its effects. Human umbilical vein endothelial cells (HUVEC) exhibited significant levels of apoptosis after serum deprivation. HGF inhibited apoptosis in a dose dependent manner in serum-deprived cultures. HGF induced the phosphorylation of Akt and Erk1/2, cell survival factors, in a time dependent manner in serum deprived HUVEC. Inhibition of Akt and Erk1/2 activation abolished the anti-apoptotic effects of HGF. The transcription factor, NF-kappaB, can also play a role in promoting cell survival. However, NF-kappaB does not appear to contribute to the anti-apoptotic properties of HGF, as nuclear translocation of NF-kappaB was not detected in HGF-treated cultures. Endothelial cell migration, proliferation, and apoptosis contribute to the pathogenesis of atherosclerosis, and HGF may play a role in the development and progression of vascular lesions. Immunohistochemical analysis of human carotid artery sections demonstrated HGF protein localization within atherosclerotic lesions but not in normal vessels, suggesting that HGF may participate in atherogenesis.

Apoptosis↗