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NADPH oxidase (NOX) is a major source of reactive oxygen species (ROS) in the body and it plays a key role in mediation of oxidative injury in the cardiovascular system. The purposes of this study are to evaluate the status of NOX in endothelial progenitor cells (EPCs) of hyperlipidemic rats and to determine whether NOX-derived ROS promotes the dysfunction of EPCs. The rats were fed on a high-fat diet for 8 weeks to establish a hyperlipidemic rat model, which showed the increased plasma lipids and the impaired functions of circulating EPCs (including the reduced abilities in migration and adhesion) accompanied by an increase in NOX activity and ROS production. Next, EPCs were isolated from normal rats and they were treated with oxidized low-density lipoprotein (ox-LDL) (100 [micro]g/mL) for 24 h to induce a dysfunctional model in vitro. In agreement with our findings in vivo, ox-LDL treatment increased the dysfunctions of EPCs concomitant with an increase in NOX activity and ROS production; these phenomena were reversed by the NOX inhibitor. Based on these observations, we conclude that NOX-derived ROS involved in the dysfunctions of circulating EPCs in hyperlipidemic rats and inhibition of NOX might provide a novel strategy to improve EPC functions in hyperlipidemia. Key words: hyperlipidemia, NADPH oxidase, endothelial progenitor cells, reactive oxygen species, oxidized low-density lipoprotein. La NADPH oxydase (NOX) est une importante source de derives reactifs de l'oxygene (ROS) dans l'organisme, qui joue un role cle dans la mediation des lesions oxydatives dans le systeme cardiovasculaire. Cette etude avait pour buts d'evaluer le statut de la NOX dans les cellules endotheliales progenitrices (CEP) de rats hyperlipidemiques et d'etablir si les ROS derives de la NOX favorisent le dysfonctionnement des CEP. Nous avons donc administre aux rats un regime haute teneur en matieres grasses pendant 8 semaines en vue d'obtenir un modele de rat hyperlipidemique, dans lequel nous avons observe une augmentation des taux plasmatiques de lipides et une deterioration du fonctionnement des CEP en circulation (y compris de la diminution des capacites de migration et d'adherence), accompagnees d'une augmentation de l'activite de la NOX et de la production de ROS. Nous avons ensuite isole des CEP de rats normaux et nous les avons exposees ;a des lipoproteines de basse densite oxydees (LDL-ox) (a 100 [micro]g/mL) pendant 24 h en vue d'obtenir un modele dysfonctionnel in vitro. En accord avec les resultats que nous avons obtenus in vivo, l'exposition aux LDL-ox a entraine une augmentation des dysfonctionnements au niveau des CEP, qui etait concomitante ;a une augmentation de l'activite de la NOX et de la production de ROS; un inhibiteur de la NOX a permis de neutraliser ces phenomenes. D'apres ces observations, nous en arrivons la conclusion qu'en jouant un role dans le dysfonctionnement des CEP en circulation chez le rat hyperlipidemique et dans l'inhibition de la NOX, les ROS derives de la NOX pourraient permettre d'obtenir une nouvelle strategie visant ;a ameliorer le fonctionnement des CEP dans un contexte d'hyperlipidemie. [Traduit par la Redaction] Mots-cles : hyperlipidemie, NADPH oxydase, cellules endotheliales progenitrices, derives reactifs de l'oxygene, lipoproteines de basse densite oxydees., Introduction It is well known that hyperlipidemia contributes greatly to atherosclerosis and atherosclerosis-associated diseases such as coronary heart disease, hypertension, and stroke. Numerous studies from animals and humans have demonstrated [...]

Background: Recently, CELSR1 was identified by genome-wide association studies (GWAS) as a susceptibility gene for ischaemic stroke (IS) in Japanese individuals. Aim: The goal was to examine whether CELSR1 variants are associated with IS in the Chinese Han population. Subjects and methods: This study genotyped two single nucleotide polymorphisms (SNPs) of CELSR1, rs6007897 and rs4044210, in a Chinese sample of 569 IS cases and 581 controls and assessed their genotype and allele associations with IS. Results: The results showed that rs6007897 and rs4044210 variants of CELSR1 were significantly ( p < 0.01) associated with IS. These associations remained after adjustment for age, gender, smoking status, hypertension, diabetes mellitus and hypercholesterolemia. In addition, a significant association was observed of rs6007897 and rs4044210 of CELSR1 with large artery atherosclerosis (LAA), a sub-type of IS ( p < 0.01). Conclusion: Taken together, the present study has proven for the first time that CELSR1 is a susceptibility gene for IS in the Chinese Han population, especially for LAA. [ABSTRACT FROM AUTHOR]

Synaptic dysfunction is an important pathological hallmark and cause of Alzheimer's disease (AD). High-frequency stimulation (HFS)-induced long-term potentiation (LTP) has been widely used to study synaptic plasticity, with impaired LTP found to be associated with AD. However, the exact molecular mechanism underlying synaptic plasticity has yet to be completely elucidated. Whether genes regulating synaptic plasticity are altered in AD and contribute to disease onset also remains unclear. Herein, we induced LTP in the hippocampal CA1 region of wild-type (WT) and AD model mice by administering HFS to the CA3 region and then studied transcriptome changes in the CA1 region. We identified 89 genes that may participate in normal synaptic plasticity by screening HFS-induced differentially expressed genes (DEGs) in mice with normal LTP, and 43 genes that may contribute to synaptic dysfunction in AD by comparing HFS-induced DEGs in mice with normal LTP and AD mice with impaired LTP. We further refined the 43 genes down to 14 by screening for genes with altered expression in pathological-stage AD mice without HFS induction. Among them, we found that the expression of Pygm , which catabolizes glycogen, was also decreased in AD patients. We further demonstrated that down-regulation of PYGM in neurons impaired synaptic plasticity and cognition in WT mice, while its overexpression attenuated synaptic dysfunction and cognitive deficits in AD mice. Moreover, we showed that PYGM directly regulated energy generation in neurons. Our study not only indicates that PYGM-mediated energy production in neurons plays an important role in synaptic function, but also provides a novel LTP-based strategy to systematically identify genes regulating synaptic plasticity under physiological and pathological conditions.

Objective: To explore the role of NADPH oxidase inhibitor apocynin on ischemia/reperfusion (I/R)-induced myocardial injury., Methods: Male SD rat hearts were divided into the normal control group; sham group; I/R group (1 h ischemia followed by 3 h reperfusion); I/R + apocynin group (50 mg/kg, administrated at 30 min before reperfusion) and I/R + vehicle group (same volume vehicle administrated at 30 min before reperfusion). At the end of reperfusion, myocardial infarct size, apoptosis, plasma CK activity, myocardial NOX activity, myocardial caspase-3 expression and activity, myocardial mRNA and protein expressions of vascular peroxidase 1 (VPO1) and NOX2 were measured., Results: Infarct size, ratio of cardiomyocyte apoptosis, mRNA and protein expression of VOP1 and NOX2, serum CK, myocardial NOX and caspase-3 activities in the I/R group were all significantly increased compared to those in the sham group (P < 0.01). Above parameters were similar between I/R + vehicle group and I/R group (all P > 0.05). Infarct size, ratio of cardiomyocyte apoptosis, myocardial mRNA and protein expression of VOP1 and NOX2, serum CK, myocardial NOX and caspase-3 activities were significantly lower in I/R + apocynin group compared to those in I/R group (all P < 0.01)., Conclusions: NOX/VPO pathway plays an important role in mediating I/R-induced myocardial oxidative injury. NOX inhibition could reduce I/R-induced myocardial oxidative injury by attenuating myocardial apoptosis in this model.

Objective: To study the effects of insulin like growth factor-1 (IGF-1) on cell viability and tissue factor (TF) in angiotensin II (Ang II) induced vascular endothelial cells and to investigate its mechanisms., Methods: 10(-6) mol/L Ang II was added to human vascular endothelial cells (HUVECs) culture media alone or 30 min after pretreatment with IGF-1 (0.1 microg/ml , 0.5 microg/ml, 2.5 microg/ml). Cell viability and AngII type 1 receptor (AT1-R) mRNA were evaluated after 24 h incubation with AngII. At the optimum concentration of IGF-1 affecting cell viability, the time dependent manner for 12 - 48 h incubation with Ang II was evaluated. TF, NOS and NO were investigated after 24 h incubation with Ang II. In addition, NO synthase inhibitor Nomega-nitro-1-arginine methylester(L-NAME) was added 30 min before addition of IGF-1 and Ang II, and cell viability, TF, AT1-R mRNA, NOS and NO were evaluated after 24 h incubation., Results: (1) Ang II induced a decrease in cell vitality, an upregulation of AT1-R mRNA, an increase in TF, and a decrease in the activity of NOS and content of NO. (2) Pretreatment with IGF-1 significantly inhibited the decreased cell viability and upregulation of AT1-R mRNA. IGF-1 at 0.5 microg/ml showed the most obvious effects. This effect of cell viability recovery was in a time dependent manner during 12 -48 h. (3) IGF-1 also inhibited the increased content of TF, the decreased activity of NOS and the decreased content of NO. (4) The beneficial effects of IGF-1 on cultured endothelial cells were completely abolished by L-NAME., Conclusion: IGF-1 pretreatment could enhance the ang II injured cell viability and anti-thrombosis capacity, and the protective effects may be related to activation of NOS-NO signaling pathway which inhibited AT1-R.

Objective: To determine the effects of Tongxinluo on cell viability and tissue factor (TF) in AngII induced vascular endothelial cells and to investigate its mechanism., Methods: AngII(10(-6)mol/L) was added to human vascular endothelial cells (HUVECs) culture media alone or with various concentration of Tongxinluo drug containing plasma (5%,10%, and 20%) added 30 minutes before AngII. Cell viability was evaluated after 24-hour incubation with AngII in a dose manner. TF, AngII type 1 receptor (AT(1)) mRNA, NO synthase (NOS) and NO were observed after 24-hour incubation with AngII. In addition, NOS inhibitor nomega-nitro-larginine (L-NAME) was added 30 minutes before Tongxinluo and AngII. Cell viability, TF, AT(1)mRNA, the level of NOS and NO were evaluated after 24-hour incubation with Tongxinluo and AngII., Results: Tongxinluo significantly improved AngII induced endothelial cell viability and the effect was the most obvious at 10%. Tongxinluo (10%) decreased the TF and AT(1) mRNA while increased the NOS and NO levels. L-NAME obviously inhibited the effects of Tongxinluo on cell viability, TF, AT(1) mRNA, and NOS and NO levels., Conclusion: Up-regulating NOS-NO signaling may be the mechanism of Tongxinluo on cell viability and TF in AngII induced vacular endothelial cells.

Objective: To determine the effect of different doses of atorvastatin on the serum soluble intercellular adhesion molecules-1 (sICAM-1) in patients undergoing percutaneous coronary intervention (PCI)., Methods: The study consisted of 38 patients with unstable angina and 10 patients with old infarction who underwent elected PCI for stenotic lesions of the coronary artery. Patients were randomly assigned to either aggressive group or conventional one. After PCI the patients took atorvastatin 20 mg per day or 10 mg per day. Blood lipid profile was examined before, and 3 months after the PCI. SICAM-1 was examined before the PCI, 48 hours and 3 months after the PCI., Results: The total cholesterol and LDL-Cholesterol 3 months after the PCI in the 2 groups were lower than those before the PCI (P<0.01). The aggressive group showed greater reduction in concentrations of TC and LDL-C than the conventional group (P<0.01). The changes in concentrations of HDL-C between pre-PCI and 3 months after the PCI and TG were not obvious (P>0.05). sICAM-1 in the 2 groups 48 hours after the PCI significantly higher than that before the PCI (P<0.01). But sICAM-1 in the 2 groups 3 months after the PCI significantly lower than that before the PCI (P<0.01 or P<0.05). The aggressive group showed greater reduction than the conventional group (P<0.01). TC and LDL-C were positively correlated with sICAM-1(r=0.2413, r=0.2691, all P<0.05)., Conclusion: Atorvastatin 20 mg per day reduces TC, LDL-C, and sICAM-1 to a greater extent than atorvastatin 10 mg per day. The effect on sICAM-1 is partly related to reduce lipid profile.