Absence of the G protein-coupled receptor G2A in mice promotes monocyte/endothelial interactions in aorta

The G protein-coupled receptor G2A is highly expressed on macrophages and lymphocytes and has been localized to atherosclerotic plaques. We examined the role of G2A in modulating monocyte/endothelial interactions in the vessel wall. We measured adhesion of WEHI 78/24 monocytes to aortas of C57BL/6 (B6) and G2A-deficient (G2A(-/-)) mice using an ex vivo adhesion assay. G2A(-/-) mice had 10-fold elevations in adhesion of monocytes to aortas. Injection of GFP-expressing wild-type macrophages into B6 and G2A(-/-) mice in vivo showed increased macrophage accumulation in the aortic wall of G2A(-/-) mice. We isolated aortic endothelial cells (ECs) from B6 and G2A(-/-) mice and found a 2-fold increase in intercellular adhesion molecule-1 and E-selectin surface expression on G2A(-/-) ECs using flow cytometry. Using ELISA, we found a 3-fold increase in interleukin-6 and monocyte chemoattractant protein-1 production by G2A(-/-) ECs compared with B6 ECs. We found a dramatic increase in nuclear localization of the p65 subunit of nuclear factor kappaB in G2A(-/-) ECs. Transfection of G2A into G2A(-/-) ECs to restore normal expression levels reduced p65 nuclear localization to 35%. Restoration of G2A expression in G2A(-/-) ECs significantly reduced intercellular adhesion molecule-1 and endothelial selectin surface expression and reduced monocyte chemoattractant protein-1 and interleukin-6 production. Restoring G2A to G2A(-/-) ECs reduced monocyte adhesion by 80% compared with G2A(-/-) ECs in a flow chamber assay. Absence of G2A in endothelium results in proinflammatory signaling and increased monocyte/endothelial interactions in the aortic wall. Thus, endothelial G2A expression may aid in prevention of vascular inflammation and atherosclerosis.     

Resistin is secreted from macrophages in atheromas and promotes atherosclerosis

OBJECTIVE: Resistin belongs to a family of cysteine-rich secreted polypeptides that are mainly produced by monocytes/macrophages in humans. Recently, high concentrations of resistin were shown to induce vascular endothelial dysfunction and vascular smooth muscle cell proliferation. We examined if resistin was secreted from macrophages locally in atheromas and if it affected vascular cell function in human. METHODS AND RESULTS: Immunohistochemical staining of human vessels showed that aortic aneurysms exhibited resistin-positive staining areas along macrophage infiltration, while normal arteries and veins did not. Co-localization of resistin and CD68 (a marker for macrophages) was observed in immunofluorescent double staining of aneurysms. Resistin mRNA was expressed much higher in cultured monocytes/macrophages than in human vascular smooth muscle cells (VSMCs) and human umbilical venous endothelial cells (HUVECs). This suggested that the resistin in aneurysms originates from macrophages within the vessels. To determine the effects of resistin on atherosclerosis, HUVECs and human VSMCs were incubated with resistin (10-100 ng/mL for 4 approximately 24 h). In HUVECs, plasminogen activator inhibitor (PAI)-1 release was assayed by ELISA, while the PAI-1 and endothelin (ET)-1 mRNA levels were analyzed by Northern blotting. Both were increased significantly with resistin treatment by factors of 1.3-2.5 (p<0.05). Migratory activity of VSMCs measured by scratched wound assay also increased significantly (1.6 times, p<0.05). In summary, macrophages infiltrating atherosclerotic aneurysms secrete resistin, and resistin affects endothelial function and VSMC migration. CONCLUSIONS: Resistin secreted from macrophages may contribute to atherogenesis by virtue of its effects on vascular endothelial cells and smooth muscle cells in humans.     

High plasma resistin level is associated with enhanced highly sensitive C-reactive protein and leukocytes

OBJECTIVES: Resistin is a newly described hormone with a suggested role in insulin resistance. In humans, inflammatory cells seem to be the major source of resistin. The aim of this study was to find out whether plasma resistin concentration associates with carotid artery atherosclerosis and the risk factors of atherosclerosis. METHODS: Plasma resistin concentrations were measured in 525 Finnish middle-aged subjects among our population-based cohort. Intima-media thickness was measured from the internal carotid artery, the bifurcation enlargement, and the common carotid artery. RESULTS: Among all the subjects, the median resistin concentration was 7.07 ng/ml (interquartile range, 5.82-8.84), women having higher levels than men (P < 0.001) with median values of 7.56 ng/ml (6.18-9.19) and 6.67 ng/ml (5.63-8.31), respectively. Resistin level correlated negatively with mean intima-media thickness, internal carotid artery, and common carotid artery, but the association did not remain significant after adjustments. Plasma resistin concentration was associated positively with leukocytes (P < 0.001), highly sensitive C-reactive protein (P = 0.009), and IGF binding protein 1 (P < 0.001), but not with plasma insulin or glucose levels in analysis of covariance after adjustments for age, sex, and body mass index. CONCLUSIONS: The results imply that inflammatory factors are more important in the determination of plasma resistin concentration than plasma insulin or glucose values. Resistin is associated with proatherogenic inflammatory markers but not independently with early atherosclerosis.     

Adipokine resistin promotes in vitro angiogenesis of human endothelial cells

OBJECTIVE: Resistin may be associated with obesity and cardiovascular diseases. However, it is unknown whether resistin directly contributes to angiogenesis. In the present study, we evaluated the effects of resistin on angiogenic potential, including endothelial cell proliferation, migration, and capillary-like tube formation. METHODS: Human coronary artery endothelial cells (HCAECs) were treated with resistin. Cell proliferation was evaluated by [3H]thymidine incorporation and MTS assays. Cell migration was assessed by a modified Boyden chamber assay. Capillary-like tube formation was studied with a Matrigel model. Several gene expression levels were determined by real-time PCR. Activation of mitogen-activated protein kinases (MAPKs) was determined by Bio-Plex luminex analyzer. Basic fibroblast growth factor (bFGF) was used as a control. Human umbilical vein endothelial cells (HUVECs) and human lung microvascular endothelial cells (HMVEC-L) were also included. RESULTS: Resistin induced both endothelial proliferation and migration in a dose- and time-dependent manner with the maximal effect at 40 ng/ml. Both resistin-induced cell proliferation and migration could be effectively blocked by a resistin-neutralization antibody. In addition, resistin promoted capillary-like tube formation of HCAECs on Matrigel. Resistin also significantly upregulated the mRNA expression of vascular endothelial growth factor receptors (VEGFR-1 and VEGFR-2) and matrix metalloproteinases (MMP-1 and MMP-2) at both mRNA and protein levels. Furthermore, transient phosphorylation of ERK1/2 and p38 was observed after the addition of resistin to HCAECs. The resistin-induced cell proliferation and migration were both completely blocked by specific ERK1/2 and p38 inhibitors. CONCLUSIONS: Resistin induces human endothelial cell proliferation and migration, promotes capillary-like tube formation, upregulates the expression of VEGFRs and MMPs, and activates ERK1/2 and p38 pathways. Thus, resistin may play an important role in angiogenesis-associated vascular disorders.     

Long-term vitamin C treatment increases vascular tetrahydrobiopterin levels and nitric oxide synthase activity

In cultured endothelial cells, the antioxidant, L-ascorbic acid (vitamin C), increases nitric oxide synthase (NOS) enzyme activity via chemical stabilization of tetrahydrobiopterin. Our objective was to determine the effect of vitamin C on NOS function and tetrahydrobiopterin metabolism in vivo. Twenty-six to twenty-eight weeks of diet supplementation with vitamin C (1%/kg chow) significantly increased circulating levels of vitamin C in wild-type (C57BL/6J) and apolipoprotein E (apoE)--deficient mice. Measurements of NOS enzymatic activity in aortas of apoE-deficient mice indicated a significant increase in total NOS activity. However, this increase was mainly due to high activity of inducible NOS, whereas eNOS activity was reduced. Significantly higher tetrahydrobiopterin levels were detected in aortas of apoE-deficient mice. Long-term treatment with vitamin C restored endothelial NOS activity in aortas of apoE-deficient mice, but did not affect activity of inducible NOS. In addition, 7,8-dihydrobiopterin levels, an oxidized form of tetrahydrobiopterin, were decreased and vascular endothelial function of aortas was significantly improved in apoE-deficient mice. Interestingly, vitamin C also increased tetrahydrobiopterin and NOS activity in aortas of C57BL/6J mice. In contrast, long-term treatment with vitamin E (2000 U/kg chow) did not affect vascular NOS activity or metabolism of tetrahydrobiopterin. In vivo, beneficial effect of vitamin C on vascular endothelial function appears to be mediated in part by protection of tetrahydrobiopterin and restoration of eNOS enzymatic activity.     

Mechanism of endothelial dysfunction in apolipoprotein E-deficient mice

Endothelium-dependent relaxations mediated by NO are impaired in a mouse model of human atherosclerosis. Our objective was to characterize the mechanisms underlying endothelial dysfunction in aortas of apolipoprotein E (apoE)-deficient mice, treated for 26 to 29 weeks with a lipid-rich Western-type diet. Aortic rings from apoE-deficient mice showed impaired endothelium-dependent relaxations to acetylcholine (10(-)(9) to 10(-)(5) mol/L) and Ca(2+) ionophore (10(-)(9) to 10(-)(6) mol/L) and endothelium-independent relaxations to diethylammonium (Z)-1-(N,N-diethylamino)diazen-1-ium-1,2-diolate (DEA-NONOate, 10(-)(10) to 10(-)(5) mol/L) compared with aortic rings from C57BL/6J mice (P<0.05). By use of confocal microscopy of an oxidative fluorescent probe (dihydroethidium), increased superoxide anion (O(2)(-)) production was demonstrated throughout the aortic wall but mainly in smooth muscle cells of apoE-deficient mice. CuZn-superoxide dismutase (SOD) and Mn-SOD protein expressions were unaltered in the aorta exposed to hypercholesterolemia. A cell-permeable SOD mimetic, Mn(III) tetra(4-benzoic acid) porphyrin chloride (10(-)(5) mol/L), reduced O(2)(-) production and partially normalized relaxations to acetylcholine and DEA-NONOate in apoE-deficient mice (P<0.05). [(14)C]L-Citrulline assay showed a decrease of Ca(2+)-dependent NOS activity in aortas from apoE-deficient mice compared with C57BL/6J mice (P<0.05), whereas NO synthase protein expression was unchanged. In addition, cGMP levels were significantly reduced in the aortas of apoE-deficient mice (P<0.05). Our results demonstrate that in apoE-deficient mice on a Western-type fat diet, impairment of endothelial function is caused by increased production of O(2)(-) and reduced endothelial NO synthase enzyme activity. Thus, chemical inactivation of NO with O(2)(-) and reduced biosynthesis of NO are key mechanisms responsible for endothelial dysfunction in aortas of atherosclerotic apoE-deficient mice.     

抵抗素的研究进展

抵抗素是存在于血浆中的富含半胱氨酸的分泌性蛋白。新近研究表明,抵抗素可作用于脂肪、肝脏、骨骼肌等胰岛素靶器官,通过影响胰岛素信号转导途径及代谢相关酶的转录影响糖、脂代谢,参与机体的能量调节。人抵抗素主要在外周血单核细胞中表达。抵抗素可作用于血管内皮细胞及平滑肌细胞影响其功能。临床研究显示,抵抗素与多个炎症标志相关,与动脉粥样硬化的病变范围关系密切,提示抵抗素可能在动脉粥样硬化的发病机制中发挥作用。     

Aerobic Exercise Prevents Insulin Resistance Through the Regulation of miR-492/Resistin Axis in Aortic Endothelium

Previously, we found that miR-492 delayed the progression of atherosclerosis (AS) by acting as an up-stream regulator of resistin. Therefore, we hypothesized that the anti-atherogenic effects of exercise are related to miR-492-mediated downregulation of resistin and repair of endothelial injury. In this study, we investigated the effects of the miR-492/resistin axis on improving endothelial injury in ApoE?/? mice (ApoE-deficient/knockout in C57BL/6 mice) through swimming exercises. Our results showed that the severity of AS and insulin resistance (IR) in these mice were significantly reduced by swimming exercises. In addition, miR-492 expression in the aortic endothelium of ApoE?/? mice was decreased, in addition to increased levels of resistin. Interestingly, swimming exercises increased miR-492 expression while decreasing that of resistin. Taken together, swimming exercises delayed the progression of AS, possibly by upregulating miR-492 and downregulating resistin in aortic endothelium. Therefore, exercises modulated glucose and lipid metabolism, alleviated endothelial IR, and repaired endothelial injury.     

Elevated resistin levels induce central leptin resistance and increased atherosclerotic progression in mice

Aims/hypothesis

Resistin was originally identified as an adipocyte-derived factor upregulated during obesity and as a contributor to obesity-associated insulin resistance. Clinically, resistin has also been implicated in cardiovascular disease in a number of different patient populations. Our aim was to simultaneously address these phenomena.

Methods

We generated mice with modest adipocyte-specific resistin overexpression. These mice were crossed with mice deficient in the LDL receptor (Ldlr ^?/?) to probe the physiological role of resistin. Both metabolic and atherosclerotic assessments were performed.

Results

Resistin overexpression led to increased atherosclerotic progression in Ldlr ^?/? mice. This was in part related to elevated serum triacylglycerol levels and a reduced ability to clear triacylglycerol upon a challenge. Additional phenotypic changes, such as increased body weight and reduced glucose clearance, independent of the Ldlr ^?/? background, confirmed increased adiposity associated with a more pronounced insulin resistance. A hallmark of elevated resistin was the disproportionate increase in circulating leptin levels. These mice thus recapitulated both the proposed negative cardiovascular correlation and the insulin resistance. A unifying mechanism for this complex phenotype was a resistin-mediated central leptin resistance, which we demonstrate directly both in vivo and in organotypic brain slices. In line with reduced sympathetic nervous system outflow, we found decreased brown adipose tissue (BAT) activity. The resulting elevated triacylglycerol levels provide a likely explanation for accelerated atherosclerosis.

Conclusions/interpretation

Resistin overexpression leads to a complex metabolic phenotype driven by resistin-mediated central leptin resistance and reduced BAT activity. Hypothalamic leptin resistance thus provides a unifying mechanism for both resistin-mediated insulin resistance and enhanced atherosclerosis.     

Acute inhibition of guanosine triphosphate cyclohydrolase 1 uncouples endothelial nitric oxide synthase and elevates blood pressure

GTP cyclohydrolase 1 (GTPCH1) is the rate-limiting enzyme in de novo synthesis of tetrahydrobiopterin (BH4), an essential cofactor for endothelial NO synthase (eNOS) dictating, at least partly, the balance of NO and superoxide produced by this enzyme. The aim of this study was to determine the effect of acute inhibition of GTPCH1 on BH4, eNOS function, and blood pressure (BP) in vivo. Exposure of bovine or mouse aortic endothelial cells to GTPCH1 inhibitors (2,4-diamino-6-hydroxypyrimidine or N-acetyl-serotonin) or GTPCH1 small-interference RNA (siRNA) significantly reduced BH4 and NO levels but increased superoxide levels. This increase was abolished by sepiapterin (BH4 precursor) or N(G)-nitro-L-arginine methyl ester (nonselective NOS inhibitor). Incubation of isolated murine aortas with 2,4-diamino-6-hydroxypyrimidine or N-acetyl-serotonin impaired acetylcholine-induced endothelium-dependent relaxation but not endothelium-independent relaxation. Aortas from GTPCH1 siRNA-injected mice, but not their control-siRNA injected counterparts, also exhibited impaired endothelium-dependent relaxation. BH4 reduction induced by GTPCH1 siRNA injection was associated with increased aortic levels of superoxide, 3-nitrotyrosine, and adhesion molecules (intercellular adhesion molecule 1 and vascular cell adhesion molecule 1), as well as a significantly elevated systolic, diastolic, and mean BP in C57BL6 mice. GTPCH1 siRNA was unable to elicit these effects in eNOS(-/-) mice. Sepiapterin supplementation, which had no effect on high BP in eNOS(-/-) mice, partially reversed GTPCH1 siRNA-induced elevation of BP in wild-type mice. In conclusion, GTPCH1 via BH4 maintains normal BP and endothelial function in vivo by preserving NO synthesis by eNOS.     

Resistin is an inflammatory marker of inflammatory bowel disease in humans

OBJECTIVES: Resistin, a recently discovered adipokine, has been shown to be associated with inflammatory conditions such as insulin resistance, obesity, atherosclerosis and rheumatoid arthritis. We therefore hypothesized that (i) resistin levels may be elevated in patients with inflammatory bowel disease (IBD) and (ii) resistin levels may be associated with disease activity in IBD. METHODS: We addressed these questions by testing for associations between resistin plasma levels, inflammatory parameters and clinical disease activity in a case-control study with 235 patients with Crohn's disease (CD), 112 patients with ulcerative colitis (UC) and 144 healthy controls. RESULTS: Patients with IBD showed significantly higher resistin levels compared with controls (P<0.0001). In both, patients with CD and UC, resistin concentrations were significantly associated with elevated white blood cell count (P<0.0001), C-reactive protein (CRP) (P<0.0001) and disease activity (P< or =0.0001). In multivariate logistic regression analysis, resistin levels were identified as an independent predictor of active disease (odds ratio 1.014, 95% confidence interval 1.002-1.027, P=0.02) in patients with CD after adjusting for sex, age, body mass index, white blood cell count and CRP. In UC patients, resistin was associated with active disease in multivariate regression analysis after control for sex, age, body mass index and white blood cell count (odds ratio 1.015, 95% confidence interval 1.002-1.029, P=0.02). Addition of CRP, however, abolished this association. CONCLUSION: Resistin levels are an independent predictor of disease activity in patients with CD. Resistin may represent a novel link between inflammation and IBD.     

Endothelin ETA receptor blockade restores NO-mediated endothelial function and inhibits atherosclerosis in apolipoprotein E-deficient mice

This study investigated whether endothelin-1 (ET-1), a potent vasoconstrictor, which also stimulates cell proliferation, contributes to endothelial dysfunction and atherosclerosis. Apolipoprotein E (apoE)-deficient mice and C57BL/6 control mice were treated with a Western-type diet to accelerate atherosclerosis with or without ET_A receptor antagonist LU135252 (50 mg/kg/d) for 30 wk. Systolic blood pressure, plasma lipid profile, and plasma nitrate levels were determined. In the aorta, NO-mediated endothelium-dependent relaxation, atheroma formation, ET receptor-binding capacity, and vascular ET-1 protein content were assessed. In apoE-deficient but not C57BL/6 mice, severe atherosclerosis developed within 30 wk. Aortic ET-1 protein content (P < 0.0001) and binding capacity for ET_A receptors was increased as compared with C57BL/6 mice. In contrast, NO-mediated, endothelium-dependent relaxation to acetylcholine (56 ± 3 vs. 99 ± 2%, P < 0.0001) and plasma nitrate were reduced (57.9 ± 4 vs. 93 ± 10 μmol/liter, P < 0.01). Treatment with the ET_A receptor antagonist LU135252 for 30 wk had no effect on the lipid profile or systolic blood pressure in apoE-deficient mice, but increased NO-mediated endothelium-dependent relaxation (from 56 ± 3 to 93 ± 2%, P < 0.0001 vs. untreated) as well as circulating nitrate levels (from 57.9 ± 4 to 80 ± 8.3 μmol/liter, P < 0.05). Chronic ET_A receptor blockade reduced elevated tissue ET-1 levels comparable with those found in C57BL/6 mice and inhibited atherosclerosis in the aorta by 31% without affecting plaque morphology or ET receptor-binding capacity. Thus, chronic ET_A receptor blockade normalizes NO-mediated endothelial dysfunction and reduces atheroma formation independent of plasma cholesterol and blood pressure in a mouse model of human atherosclerosis. ET_A receptor blockade may have therapeutic potential in patients with atherosclerosis.     

Endothelial Nox2 overexpression potentiates vascular oxidative stress and hemodynamic response to angiotensin II: studies in endothelial-targeted Nox2 transgenic mice

Vascular disease states are associated with endothelial dysfunction and increased production of reactive oxygen species (ROS) derived from vascular NADPH oxidases in both vascular smooth muscle cells (VSMCs) and endothelial cells. Recent evidence suggests an important role for VSMC NADPH oxidases in vascular ROS production. However, it is unclear whether increased NADPH oxidase activity in endothelial cells alone is sufficient to alter overall vascular ROS production and hemodynamics. We sought to address these questions using transgenic mice with endothelial-targeted overexpression of the catalytic subunit of NADPH oxidase, Nox2. Aortas of Nox2 transgenic (Nox2-Tg) mice had increased total Nox2 mRNA and protein levels compared with wild-type littermates. Both p22phox mRNA and protein levels were also significantly elevated in Nox2-Tg aortas. Aortic superoxide production was significantly increased in Nox2-Tg mice compared with wild-type, but this difference was abolished by endothelial removal. Superoxide dismutase inhibition increased superoxide release and levels of Mn superoxide dismutase protein were significantly elevated in aortas from Nox2-Tg mice compared with wild type. Increased ROS production from endothelial Nox2 overexpression led to increased endothelial nitric oxide synthase protein and extracellular signal-regulated kinase 1/2 phosphorylation in transgenic aortas. Basal blood pressure was similar, however the pressor responses to both acute and chronic angiotensin II administration were significantly increased in Nox2-Tg mice compared with wild type. These results demonstrate that endothelial-targeted Nox2 overexpression is sufficient to increase vascular NADPH oxidase activity, activate downstream signaling pathways, and potentiate the hemodynamic response to angiotensin II, despite compensatory increases in vascular antioxidant enzymes. Endothelial cell Nox2-containing NADPH oxidase plays an important functional role in vascular redox signaling.     

Pitavastatin improves serum resistin levels in patients with hypercholesterolemia

AIM: Resistin in serum is associated with high risk in patients with atherosclerosis. This clinical study aimed to investigate whether pitavastatin can regulate the serum level of resistin, together with levels of other inflammatory cytokines and adipocytokines. METHODS: Forty two outpatients (mean age 65.2 +/- 12.6 yr, M/F: 21/21) with hypercholesterolemia were administered 2 mg of pitavastatin and serum levels of resistin, together with serum levels of adiponectin, leptin, TNF-alpha and hsCRP, were measured before, and 12 weeks after enrollment. RESULTS: There was no significant gender-related difference in initial serum resistin levels. Pitavastatin significantly decreased LDL-cholesterol after 12 weeks. Initial levels of resistin showed a significant correlation with those of hsCRP (r=0.38, p=0.013), but not TNF-alpha or HOMA-R. Serum resistin, but not adiponectin and leptin, levels were significantly decreased, dropping from 17.1 +/- 9.9 ng/ dL to 15.2+/-10.0 (p=0.001) after 12 weeks of administration. The patient group with a baseline hsCRP > or = 0.1 at enrollment (n=17) had decreased levels of both resistin and hsCRP (p=0.011 and p=0.022, respectively). CONCLUSION: This study showed the pleiotropic effect of pitavastatin on the serum resistin concentration, suggesting that it may assist in the prevention of atherosclerosis.     

p21Cip1 levels differentially regulate turnover of mature endothelial cells, endothelial progenitor cells, and in vivo neovascularization

p21(Cip1) (p21) controls cell cycle progression and apoptosis in mature endothelial cells (ECs) and regulates size and cycling of the hematopoietic progenitor cell pool. Because circulating endothelial progenitor cells (EPCs) contribute to postnatal neovascularization in addition to mature ECs, we investigated the regulation of ECs and EPCs in p21-deficient mice. Mature aortic EC proliferation was increased in homozygous p21(-/-) and heterozygous p21(+/-) mice, in which p21 protein levels are reduced to one third of wild-type (WT). In contrast, apoptosis sensitivity was increased by 3.5-fold only in p21(-/-), but not in p21(+/-) mice. Consistently, in vivo apoptosis of ECs within areas of neovascularization was elevated in p21(-/-) but not in p21(+/-) mice. EPC numbers were elevated 2-fold in p21(-/-) mice compared with WT (P<0.001), and clonal expansion capacity of EPCs was increased from 25+/-4 (WT) to 57+/-8 colony-forming units in p21(-/-) mice (P<0.005). EPC numbers and expansion were likewise increased in p21(+/-) mice. As the integrative endpoint, in vivo neovascularization reflecting all p21-affected parameters was increased over WT only in p21(+/-) (P<0.001), but not in p21(-/-) mice. In conclusion, reduced p21 protein levels of mice lacking one p21 allele are associated with increased proliferation of ECs and EPCs, whereas survival of ECs to apoptotic stimuli in vitro and in vivo is not impaired. Under these conditions, neovascularization was increased. In contrast, complete p21 deficiency did not result in an increased neovascularization despite increased mature EC and EPC proliferation. This may be due to the sensitization of ECs against apoptosis.     

Transplantation of vascular endothelial cells mediates the hematopoietic recovery and survival of lethally irradiated mice

Flk-1(+) endothelial progenitors contribute critically to the definitive onset of hematopoiesis during embryogenesis. Recent studies have suggested that adult sources of endothelial cells also possess hematopoietic activity. In this study, we sought to determine whether transplantation of primary vascular endothelial cells (ECs) could enhance the hematopoietic recovery and survival of irradiated mice. C57Bl6 mice were exposed to sublethal and lethal doses of irradiation and were subsequently given transplants of either primary murine brain-derived ECs (MBECs) or fetal blood-derived ECs (FBECs). Mice that received a transplant with MBECs alone demonstrated accelerated BM cellular recovery, radioprotection of BM c-kit(+)sca-1(-)lin(-) progenitors and enhanced regeneration of c-kit(+)sca-1(+)lin(-) (KSL) stem/progenitor cells following irradiation compared with controls. MBEC transplantation also facilitated the recovery of circulating white blood cell and platelet counts following radiation exposure. Remarkably, 57% of mice that received a transplant with MBECs alone survived long term following 1050 cGy exposure, which was 100% lethal in control mice. FBEC transplantation was also associated with increased survival compared with controls, although these mice did not survive in the long term. These data suggest that reestablishment of endothelial cell activity can improve the hematopoietic recovery and survival of irradiated mice.     

Dietary ellagic acid improves oxidant-induced endothelial dysfunction and atherosclerosis: Role of Nrf2 activation

Background

Oxidative stress-induced vascular endothelial cell injury is a major factor in the pathogenesis of atherosclerosis. Several evidences indicate that ellagic acid (EA), a phenolic compound, contributes to cardiovascular health. This study was to investigate the effects of EA on endothelial dysfunction and atherosclerosis via antioxidant-related mechanisms.

Methods

In animal studies, wild-type (WT) C57BL/6 mice and apolipoprotein E-deficient mice (ApoE^−/−) mice were fed: a high-fat (21%) diet (HFD) or a HFD plus with EA (HFD + EA), for 14 weeks. Vascular reactivity was studied in mice aortas. The effect of EA in human umbilical vein endothelial cells (HAECs) exposed to hypochlorous acid (HOCl) was also investigated.

Results

Compared with animals on HFD alone, EA attenuated atherosclerosis in WT mice. In aortic rings from two mice models, EA significantly improved endothelium-dependent relaxation and attenuated HOCl-induced endothelial dysfunction. Besides, EA significantly improved nitric oxide synthase activity, antioxidant capacity and markers of endothelial dysfunction in plasma. Western blot analysis showed that EA increased NF-E2-related factor 2 (Nrf2) and heme oxygenase-1(HO-1) expression in the aortas (P < 0.05). In a separate experiment, EA did not protect against HOCl-induced endothelial dysfunction in arteries obtained from Nrf2 gene knockout mice compared with WT mice. In HAECs, EA prevented HOCl-induced cellular damage and induced HO-1 protein expression, and these effects markedly abolished by the siRNA of Nrf2.

Conclusions

Our results provide further support for the protective effects of dietary EA particularly oxidant-induced endothelial dysfunction and atherosclerosis partly via Nrf2 activation.     

Resistin, acute coronary syndrome and prognosis results from the AtheroGene study

OBJECTIVE: Resistin, an adipocyte and macrophage derived cytokine, causes insulin resistance and glucose intolerance. We investigated the impact of resistin as a diagnostic marker in patients with acute coronary syndrome and its prognostic value for future cardiovascular events. METHODS: Resistin levels were determined in 1153 patients with stable angina (SAP), 380 patients with unstable angina, 278 patients with non-ST-elevation myocardial infarction (NSTEMI) and 111 patients with ST-elevation myocardial infarction (STEMI). All patients have been followed up for a median follow-up of 2.6 years. During follow-up, 70 patients died from cardiovascular causes. RESULTS: Compared to SAP, resistin levels (5.1 ng/mL in SAP) were elevated in patients with angina at rest (5.89 ng/mL, P=0.001), in patients with NSTEMI (6.00 ng/mL, P<0.001), and in patients with STEMI (5.98 ng/mL, P<0.001). Resistin levels rose at 3-6h after chest pain onset (5.46 ng/mL), persisted elevated among those individuals presenting between 6 and 12h after chest pain onset (5.57 ng/mL) and peaked in individuals presenting more than 12h after chest pain onset (5.74 ng/mL). An increase of one standard deviation of resistin levels was associated with a 1.22-fold (95% CI 1.04-1.43; P=0.02) risk for future fatal cardiovascular events in a model adjusted for risk factors and clinical and therapeutic variables. When adjustment for renal function was applied, this association lost its statistical significance. CONCLUSIONS: Resistin levels are elevated in patients presenting with unstable angina, NSTEMI and STEMI and might play a role as a diagnostic marker. In addition, systemic resistin level is moderately associated with future cardiovascular death in patients with documented coronary artery disease.     

Plasma resistin levels in asthmatics as a marker of disease state.

BACKGROUND: Resistin is a protein produced by adipocytes and circulating macrophages that has been found to be associated with inflammatory states. OBJECTIVE: To determine the levels of resistin in relation to asthma disease state and severity, we investigated a cohort of adult patients with asthma. METHODS: A cohort of moderate to severe persistent asthma patients and control patients were recruited and underwent fasting labs to evaluate levels of serum glucose, C-reactive protein (CRP), and resistin. RESULTS: No significant differences were found between the control and asthma group with respect to serum CRP at 0.78 +/- 0.60 mg/dL and 0.48 +/- 0.60 mg/dL, (p < 0.36) or glucose at 92.2 +/- 11.9 mg/dL and 89.5 +/- 7.2 mg/dL, (p < 0.084), respectively (mean +/- SD). However, plasma resistin levels were found to be significantly elevated in asthma patients, 186 ng/mL (95%CI 169-202) compared with control patients 121 ng/mL (95%CI 90.4-151), (p < 0.005). CONCLUSIONS: Patients with asthma were found to have higher levels of resistin, and resistin levels were increased with disease severity in the asthma cohort.