Arteriosclerosis, Thrombosis, and Vascular Biology
Công bố khoa học tiêu biểu
Sắp xếp:
Caffeine Enhances Endothelial Repair by an AMPK-Dependent Mechanism
Objective—
Migratory capacity of endothelial progenitor cells (EPCs) and mature endothelial cells (ECs) is a key prerequisite for endothelial repair after denuding injury or endothelial damage.
Methods and Results—
We demonstrate that caffeine in physiologically relevant concentrations (50 to 100 μmol/L) induces migration of human EPCs as well as mature ECs. In patients with coronary artery disease (CAD), caffeinated coffee increased caffeine serum concentration from 2 μmol/L to 23 μmol/L, coinciding with a significant increase in migratory activity of patient-derived EPCs. Decaffeinated coffee neither affected caffeine serum levels nor migratory capacity of EPCs. Treatment with caffeine for 7 to 10 days in a mouse-model improved endothelial repair after denudation of the carotid artery. The enhancement of reendothelialization by caffeine was significantly reduced in AMPK knockout mice compared to wild-type animals. Transplantation of wild-type and AMPK
−/−
bone marrow into wild-type mice revealed no difference in caffeine challenged reendothelialization. ECs which were depleted of mitochondrial DNA did not migrate when challenged with caffeine, suggesting a potential role for mitochondria in caffeine-dependent migration.
Conclusion—
These results provide evidence that caffeine enhances endothelial cell migration and reendothelialization in part through an AMPK-dependent mechanism, suggesting a beneficial role for caffeine in endothelial repair.
Arteriosclerosis, Thrombosis, and Vascular Biology - Tập 28 Số 11 - Trang 1967-1974 - 2008
Cell-Based Therapy of Myocardial Infarction Cell-based therapy is a promising option for treatment of ischemic diseases. Several cell types have experimentally been shown to increase the functional recovery of the heart after ischemia by physically forming new blood vessels, differentiating to cardiac myocytes and—additionally or alternatively—by providing proangiogenic and antiapoptotic factors promoting tissue repair in a paracrine manner. Clinical studies preferentially used adult bone marrow–derived cells for the treatment of patients with acute myocardial infarction. Most of the studies suggested that cell therapy reduced the infarct size and improved cardiac contractile function. However, cell therapy is in its early stages, and various questions remain. For example, the identification of those patients who benefit most from cell therapy, the optimal cell type and number for patient with acute and chronic diseases, the best time and way of cell delivery, and the mechanisms of action by which cells exhibit beneficial effects, need to be further evaluated. Although no major safety concerns were raised during the initial clinical trials, several potential side effects need to be carefully monitored. The present review article summarizes the results of the clinical studies and discusses the open issues.
Arteriosclerosis, Thrombosis, and Vascular Biology - Tập 28 Số 2 - Trang 208-216 - 2008
Lymphocyte Populations in Atherosclerotic Lesions of ApoE −/− and LDL Receptor −/− Mice Lymphocytes are prominent components of human atherosclerotic lesions, but their presence in murine models of disease has not been confirmed. Lymphocyte subpopulations have been identified in apoE −/− and LDL receptor −/− mice fed a cholesterol-enriched diet for up to 3 months. ApoE −/− mice had higher serum cholesterol concentrations than did LDL receptor −/− mice during most of the feeding period, primarily due to large increases in VLDL concentrations. Total area of atherosclerotic lesions was greater at all times in apoE −/− than LDL receptor −/− mice (lesion area after 3 months on cholesterol-enriched diet: apoE −/−, 993±193 and LDL receptor −/−, 560±131 μm2 ×103 , mean±SEM, n=6 in each group). Lesions in apoE −/− mice contained larger macrophage-rich necrotic cores and more calcification than did those in LDL receptor −/− mice. Immunocytochemical analyses of tissue sections of ascending aortas performed with monoclonal antibodies to T and B lymphocytes and macrophages revealed that T lymphocytes immunoreactive for Thy 1.2, CD5, CD4, and CD8 were observed in lesions from both strains, but no B lymphocytes were detected. The density of Thy 1.2+ T lymphocytes in lesions was greatest at 1 month (apoE −/−, 98±23 and LDL receptor −/−, 201±40 lymphocytes/mm2 , n=6 in each group), decreasing in apoE −/− mice to 12±3 and in LDL receptor −/− mice to 51±20 lymphocytes/mm2 at 3 months. The presence of T lymphocytes in murine atherosclerotic lesions makes these animals potentially useful for studying the involvement of the immune system in atherogenesis.
Arteriosclerosis, Thrombosis, and Vascular Biology - Tập 16 Số 8 - Trang 1013-1018 - 1996
Neutrophil Extracellular Traps Promote Thrombin Generation Through Platelet-Dependent and Platelet-Independent Mechanisms
Objective—
Activation of neutrophils by microbial or inflammatory stimuli results in the release of neutrophil extracellular traps (NETs) that are composed of DNA, histones, and antimicrobial proteins. In purified systems, cell-free DNA (CFDNA) activates the intrinsic pathway of coagulation, whereas histones promote thrombin generation through platelet-dependent mechanisms. However, the overall procoagulant effects of CFDNA/histone complexes as part of intact NETs are unknown. In this study, we examined the procoagulant potential of intact NETs released from activated neutrophils. We also determined the relative contribution of CFDNA and histones to thrombin generation in plasmas from patients with sepsis.
Approach and Results—
NETs released from phorbyl myristate–activated neutrophils enhance thrombin generation in platelet-poor plasma. This effect was DNA dependent (confirmed by DNase treatment) and occurred via the intrinsic pathway of coagulation (confirmed with coagulation factor XII– and coagulation factor XI–depleted plasma). In platelet-rich plasma treated with corn trypsin inhibitor, addition of phorbyl myristate–activated neutrophils increased thrombin generation and shortened the lag time in a toll-like receptor-2– and toll-like receptor-4–dependent mechanism. Addition of DNase further augmented thrombin generation, suggesting that dismantling of the NET scaffold increases histone-mediated, platelet-dependent thrombin generation. In platelet-poor plasma samples from patients with sepsis, we found a positive correlation between endogenous CFDNA and thrombin generation, and addition of DNase attenuated thrombin generation.
Conclusions—
These studies examine the procoagulant activities of CFDNA and histones in the context of NETs. Our studies also implicate a role for the intrinsic pathway of coagulation in sepsis pathogenesis.
Arteriosclerosis, Thrombosis, and Vascular Biology - Tập 34 Số 9 - Trang 1977-1984 - 2014
Body Fat Distribution Is a Determinant of the High-Density Lipoprotein Response to Dietary Fat and Cholesterol in Women Abstract We have conducted a dietary trial that addressed the factors influencing the variability in plasma lipids in response to dietary fat and cholesterol with a focus on the effects of gender and body fat distribution. Sixty-seven women and 53 men were selected so that overall men and women had a similar mean age, LDL cholesterol, and body mass index. After a 2-week low-fat period subjects were given two liquid supplements for 3 weeks each, one that contained 31 to 40 g fat and 650 to 845 mg cholesterol, and one that was fat free. Measurements included plasma lipids and lipoproteins, glucose, insulin, hepatic triglyceride lipase activity, apolipoprotein E polymorphism, and three indexes of body fat (body mass index, waist girth, and waist-hip ratio). In response to dietary fat and cholesterol supplementation only the changes in HDL cholesterol, especially in HDL2 , differed between the sexes. Although on univariate analysis lipoprotein changes were predicted by baseline lipoprotein levels, body mass index, waist girth, waist-hip ratio, hepatic triglyceride lipase activity, and insulin, multiple regression showed only waist-hip ratio to predict changes in HDL2 cholesterol in women and body mass index and baseline HDL2 cholesterol in men. Changes in LDL were predicted by baseline LDL cholesterol in women and apolipoprotein E phenotype and age in men. These studies explain much of the variability that individuals show in lipoprotein changes, especially in the more desirable changes in cholesterol transport in HDL2 , in response to eating saturated fat and cholesterol.
Arteriosclerosis, Thrombosis, and Vascular Biology - Tập 15 Số 8 - Trang 1070-1078 - 1995
Oxidized LDL-Induced Smooth Muscle Cell Proliferation Involves the EGF Receptor/PI-3 Kinase/Akt and the Sphingolipid Signaling Pathways
Objective—
Oxidized low-density lipoprotein (oxLDL)-induced smooth muscle cell (SMC) proliferation requires the coactivation of various signaling pathways, namely sphingomyelin/ceramide/sphingosine-1-phosphate, epithelial growth factor receptor (EGFR), and phosphoinositide 3-kinase (PI-3K) pathways. This study aimed to clarify the respective role and the hypothetical cross-talk between sphingomyelin/ceramide/sphingosine-1-phosphate, EGFR, and PI-3K/Akt pathways in the balance between mitogenic and cytotoxic effects elicited by oxLDL.
Methods and Results—
Coimmunoprecipitation experiments and the use of inhibitors and dominant-negative mutant showed that oxLDL-induced PI-3K activation is dependent on EGFR. PI-3K activation is independent of the sphingomyelin/ceramide/sphingosine-1-phosphate pathway, because PI-3K inhibition by LY294002 or dominant-negative Δp85 mutant does not abrogate sphingomyelin hydrolysis, and, conversely, the use of permeant C2-ceramide and of
N,N
-dimethyl-sphingosine, a sphingosine kinase inhibitor, does not alter PI-3K activity. Activation of Akt/PKB by oxLDL requires PI-3K, as shown by the inhibition by LY204002 and in Δp85 SMC. The inhibition of Akt/PKB by PI-3K inhibitor LY204002 or by overexpression of kinase-dead Akt shifted the mitogenic effect of oxLDL toward apoptosis, thus suggesting that the PI-3K/Akt pathway acts as a survival pathway.
Conclusions—
SMC proliferation elicited by moderate concentrations of oxLDL involves the sphingomyelin/ceramide/sphingosine-1-phosphate pathway, which leads to extracellular regulated kinase 1/2 activation and DNA synthesis, and the EGFR/PI-3K/Akt pathway, which prevents the apoptotic effect of oxLDL.
Arteriosclerosis, Thrombosis, and Vascular Biology - Tập 22 Số 12 - Trang 1990-1995 - 2002
Leukotriene Receptor Antagonism and the Prevention of Extracellular Matrix Degradation During Atherosclerosis and In-Stent Stenosis
Objective—
The lipid-derived inflammatory mediators leukotrienes (LTs) are produced during vascular injury. The aim of the present study was to determine the role of LT receptor signaling in the pathophysiology of in-stent stenosis.
Methods and Results—
New Zealand White rabbits were fed 0.3% cholesterol and subjected to angioplasty with balloon dilatation and stent implantation in the right carotid artery. Rabbits treated for 2 weeks with the BLT receptor antagonist BIIL284 (3 mg/kg once daily by oral gavage) displayed a significantly reduced in-stent intimal hyperplasia in carotid arteries compared with vehicle-treated rabbits. In addition, BIIL284 treatment significantly reduced the extracellular matrix metalloproteinase (MMP)-2 and MMP-9 activities in stented arteries. The inhibited MMP-9 activity was correlated with decreased macrophage content in the lesions. The LTB
4
-induced migration of vascular smooth muscle cells was significantly inhibited by transfection with siRNA against MMP-2. Finally, human arteries subjected to ex vivo angioplasty and stent implantation displayed an increased in-stent intimal hyperplasia and higher MMP-2 and -9 activities in the presence of LTB
4
.
Conclusions—
These results suggest a key role of LT signaling in the extracellular matrix degradation associated with hyperlipidemia and in-stent stenosis. In conclusion, targeting LT receptors may represent a therapeutic strategy in atherosclerosis and interventional cardiology.
Arteriosclerosis, Thrombosis, and Vascular Biology - Tập 29 Số 4 - Trang 518-524 - 2009
Metalloproteinase Expression in Monocytes and Macrophages and its Relationship to Atherosclerotic Plaque Instability Matrix metalloproteinases (MMPs) can degrade strength-giving collagens and other structural proteins of the arterial extracellular matrix. Overproduction of MMPs by monocyte/macrophages could therefore promote atherosclerotic plaque rupture and myocardial infarction. Freshly-recruited monocyte macrophages appear to use a prostaglandin (PG)-dependent pathway to coordinately upregulate a broad and potentially highly-destructive spectrum of MMPs. Differentiated macrophages rely on a series of distinct pathways to selectively upregulate groups of MMPs. Moreover, recent evidence suggests that different macrophage phenotypes express characteristically different spectra of MMPs and their inhibitors. New therapies may result from targeting matrix MMP overproduction.
Arteriosclerosis, Thrombosis, and Vascular Biology - Tập 28 Số 12 - Trang 2108-2114 - 2008
Association Between 5-Lipoxygenase Expression and Plaque Instability in Humans
Objective—
The participation of 5-lipoxygenase (5-LO) in the development of atherosclerosis has been suggested by recent studies. However, a role for 5-LO as a modulator of atherosclerotic plaque instability has not been previously reported in humans. Thus, the aims of this study was to analyze the expression of 5-LO in human carotid plaques and to investigate the mechanism by which this enzyme could lead to plaque instability and rupture.
Methods and Results—
We obtained atherosclerotic plaques from 60 patients undergoing carotid endarterectomy. We divided the plaques into symptomatic and symptomatic according to clinical evidence of plaque instability. Clinical evidence of plaque instability was provided by the assessment of recent ischemic symptoms attributable to the stenosis and by the presence of ipsilateral cerebral lesion(s) determined by computed tomography. Plaques were analyzed for CD68+ macrophages, CD3+ T cells, α-actin+ smooth muscle cells, 5-LO, cyclooxygenase 2, matrix metalloproteinase (MMP)-2, and MMP-9 by immunohistochemical, immunoblotting, and densitometric analyses. MMP activity was assessed by zymography. Leukotriene (LT) B
4
and collagen were quantified by ELISA and Sirius red polarization, respectively. The percentage of macrophage-rich and T-cell–rich areas was larger in symptomatic compared with asymptomatic patients (25±6% versus 8±4%,
P
<0.0001, and 74±17 versus 18±4 cell/mm
2
,
P
<0.003). 5-LO expression was higher in symptomatic compared with asymptomatic plaques (24±4% versus 6±3%,
P
<0.0001) and was associated with increased MMP-2 and MMP-9 expression (27±4% versus 7±3%,
P
<0.0001, and 29±5% versus 8±2%,
P
<0.0001) and activity and with decreased collagen content (6.9±2.4% versus 17.8±3.1%,
P
<0.01). Immunofluorescence showed that 5-LO and MMPs colocalize in activated macrophages. Notably, higher 5-LO in symptomatic plaques correlated with increased LTB
4
production (18.15±3.56 versus 11.27±3.04 ng/g tissue,
P
<0.0001).
Conclusions—
The expression of 5-LO is elevated in symptomatic compared with asymptomatic plaques and is associated with acute ischemic syndromes, possibly through the generation of LTB
4
, subsequent MMP biosynthesis, and plaque rupture.
Arteriosclerosis, Thrombosis, and Vascular Biology - Tập 25 Số 8 - Trang 1665-1670 - 2005
Two Distinct Calcium-Dependent Mitochondrial Pathways Are Involved in Oxidized LDL-Induced Apoptosis
Objective—
Oxidized low-density lipoprotein (oxLDL)-induced apoptosis of vascular endothelial cells may contribute to plaque erosion and rupture. We aimed to clarify the relationship between the oxLDL-induced calcium signal and induction of apoptotic pathways.
Methods and Results—
Apoptosis was evaluated by biochemical methods, including studies of enzyme activities, protein processing, release of proapoptotic factors, chromatin cleavage, and especially by morphological methods that evaluate apoptosis/necrosis by SYTO-13/propidium iodide fluorescent labeling. The oxLDL-induced sustained calcium rise activated 2 distinct calcium-dependent mitochondrial apoptotic pathways in human microvascular endothelial cells. OxLDLs induced calpain activation and subsequent Bid cleavage and cytochrome C release, which were blocked by calpeptin. Cyclosporin-A inhibited cytochrome C release, possibly by inhibiting the opening of the mitochondrial permeability transition pore (mPTP). Calcineurin, another cyclosporin-sensitive step, was not implicated, because oxLDLs inhibited calcineurin and FK-506 treatment was ineffective. Cytochrome C release in turn induced caspase-3 activation. In addition, oxLDLs triggered release and nuclear translocation of mitochondrial apoptosis-inducing factor through a mechanism dependent on calcium but independent of calpains, mPTP, and caspases.
Conclusions—
OxLDL-induced apoptosis involves 2 distinct calcium-dependent pathways, the first mediated by calpain/mPTP/cytochrome C/caspase-3 and the second mediated by apoptosis-inducing factor, which is cyclosporin-insensitive and caspase-independent.
Arteriosclerosis, Thrombosis, and Vascular Biology - Tập 25 Số 3 - Trang 639-645 - 2005
Tổng số: 341
- 1
- 2
- 3
- 4
- 5
- 6
- 35