Alcohol Consumption Negates Estrogen-mediated Myocardial Repair in Ovariectomized Mice by Inhibiting Endothelial Progenitor Cell Mobilization and Function

We have shown previously that estrogen (estradiol, E2) supplementation enhances voluntary alcohol consumption in ovariectomized female rodents and that increased alcohol consumption impairs ischemic hind limb vascular repair. However, the effect of E2-induced alcohol consumption on post-infarct myocardial repair and on the phenotypic/functional properties of endothelial progenitor cells (EPCs) is not known. Additionally, the molecular signaling of alcohol-estrogen interactions remains to be elucidated. This study examined the effect of E2-induced increases in ethanol consumption on post-infarct myocardial function/repair. Ovariectomized female mice, implanted with 17β-E2 or placebo pellets were given access to alcohol for 6 weeks and subjected to acute myocardial infarction. Left ventricular functions were consistently depressed in mice consuming ethanol compared with those receiving only E2. Alcohol-consuming mice also displayed significantly increased infarct size and reduced capillary density. Ethanol consumption also reduced E2-induced mobilization and homing of EPCs to injured myocardium compared with the E2-alone group. In vitro, exposure of EPCs to ethanol suppressed E2-induced proliferation, survival, and migration and markedly altered E2-induced estrogen receptor-dependent cell survival signaling and gene expression. Furthermore, ethanol-mediated suppression of EPC biology was endothelial nitric oxide synthase-dependent because endothelial nitric oxide synthase-null mice displayed an exaggerated response to post-acute myocardial infarction left ventricular functions. These data suggest that E2 modulation of alcohol consumption, and the ensuing EPC dysfunction, may negatively compete with the beneficial effects of estrogen on post-infarct myocardial repair.     

Delayed post-conditioning reduces post-ischemic glutamate level and improves protein synthesis in brain

In the clinic delayed post-conditioning would represent an attractive strategy for the survival of vulnerable neurons after an ischemic event. In this paper we studied the impact of ischemia and delayed post-conditioning on blood and brain tissue concentrations of glutamate and protein synthesis. We designed two groups of animals for analysis of brain tissues and blood after global ischemia and post-conditioning, and one for analysis of blood glutamate after transient focal ischemia.     

Laminar shear stress elicit distinct endothelial cell e‐selectin expression pattern via TNFα and IL‐1β activation

The ability to discriminate cell adhesion molecule expression between healthy and inflamed endothelium is critical for therapeutic intervention in many diseases. This study explores the effect of laminar flow on TNFα‐induced E‐selectin surface expression levels in human umbilical vein endothelial cells (HUVECs) relative to IL‐1β‐induced expression via flow chamber assays. HUVECs grown in static culture were either directly (naïve) activated with cytokine in the presence of laminar shear or pre‐exposed to 12 h of laminar shear (shear‐conditioned) prior to simultaneous shear and cytokine activation. Naïve cells activated with cytokine in static served as control. Depending on the cell shear history, fluid shear is found to differently affect TNFα‐induced relative to IL‐1β‐induced HUVEC expression of E‐selectin. Specifically, E‐selectin surface expression by naïve HUVECs is enhanced in the 8–12 h activation time range with simultaneous exposure to shear and TNFα (shear‐TNFα) relative to TNFα static control whereas enhanced E‐selectin expression is observed in the 4–24 h range for shear‐IL‐1β treatment relative to IL‐1β static control. While exposure of HUVECs to shear preconditioning mutes shear‐TNFα‐induced E‐selectin expression, it enhances or down‐regulates shear‐IL‐1β‐induced expression dependent on the activation period. Under dual‐cytokine‐shear conditions, IL‐1β signaling dominates. Overall, a better understanding of E‐selectin expression pattern by human ECs relative to the combined interaction of cytokines, shear profile and history can help elucidate many disease pathologies. Biotechnol. Bioeng. 2013; 110: 999–1003. © 2012 Wiley Periodicals, Inc.     

Bone morphogenetic protein-7 (BMP-7) mediates ischemic preconditioning-induced ischemic tolerance via attenuating apoptosis in rat brain

A mild cerebral ischemic insult, also known as ischemic preconditioning (IPC), confers transient tolerance to a subsequent ischemic challenge in the brain. This study was conducted to investigate whether bone morphogenetic protein-7 (BMP-7) is involved in neuroprotection elicited by IPC in a rat model of ischemia. Ischemic tolerance was induced in rats by IPC (15 min middle cerebral artery occlusion, MCAO) at 48 h before lethal ischemia (2 h MCAO). The present data showed that IPC increased BMP-7 mRNA and protein expression after 24 h reperfusion following ischemia in the brain. In rats of ischemia, IPC-induced reduction of cerebral infarct volume and improvement of neuronal morphology were attenuated when BMP-7 was inhibited either by antagonist noggin or short interfering RNA (siRNA) pre-treatment. Besides, cerebral IPC-induced up-regulation of B-cell lymphoma 2 (Bcl-2) and down-regulation of cleaved caspase-3 at 24 h after ischemia/reperfusion (I/R) injury were reversed via inhibition of BMP-7. These findings indicate that BMP-7 mediates IPC-induced tolerance to cerebral I/R, probably through inhibition of apoptosis.     

ERK介导的炎性反应参与肾缺血再灌注损伤

目的研究小鼠肾缺血再灌注损伤的发病机制。方法建立小鼠肾缺血再灌注损伤模型。12只雄性C57BL／6随机分为2个组（n=6）,分别为假手术组（Sham）,肾缺血再灌注损伤模型组（IRI）。IRI组血管夹夹闭左肾动脉,置于32℃温箱后1h松开血管夹,去除右肾。Sham组操作同上,但不夹闭左肾动脉。再灌注24h后处死小鼠,收集血清和肾脏标本。测定血清肌酐（Cr）和血尿素氮（BUN）。PAS染色后显微镜下观察肾脏形态学变化,Western印迹分析ERK、p-ERK的表达,PCR检测MCP-1、IFN-γ。结果与假手术组（Sham）相比,IRI组血清肌酐、血尿素氮明显升高,病理检查可见肾脏内肾小管上皮细胞明显肿胀坏死、蛋白管型形成明显,还可观察到炎性细胞浸润明显增加。ERK、p-ERKWestern印迹结果PCR显示MCP-1、TNF-α也明显上调,但ERK表达不变。结论在肾缺血再灌注中,ERK激活介导的炎性后府可能参与了肾扣伤。     

N—acetylserotonin对肝缺血再灌注小鼠氧化应激损伤的保护作用

目的探讨NAS对肝缺血再灌注所诱导的脂质过氧化损伤产生的保护作用。方法采用夹闭肝蒂法30min、再灌注6h制作肝缺血再灌注模型,冰冻切片,HE染色,光学显微镜下观察肝细胞形态结构的变化;比色法检测损伤后血清中谷丙转氨酶（ALT）水平及肝组织中超氧化物歧化酶（SOD）、丙二醛（MDA）、谷胱甘肽过氧化物酶（GSH—Px）的含量。结果夹闭肝蒂30min、再灌注6h后,肝小叶结构紊乱、肝血窦淤血,其间有白细胞浸润、肝细胞出现变性、坏死;血清中ALT水平升高,肝组织中s0D和GSH—Px的含量降低,MDA升高;NAS可减少缺血再灌注后血清ALT的释放,使肝组织中SOD和GSHPx的含量升高,MDA的含量降低;NAS＋Luz可逆转NAS的这一作用。结论NAS对肝缺血再灌注小鼠的氧化应激损伤具有保护作用。     

Ischémie myocardique du diabétique : apports de la scintigraphie myocardique de perfusion

Diabetes is an important risk factor of myocardial ischemia. Myocardial perfusion imaging (MPI) is used for diagnostic, prognostic assessment and for post-therapeutic follow-up of coronary artery disease (CAD). Its usefulness has been documented extensively in the general population. However, in diabetic population, little studies have been published. CAD is more severe and more frequent among diabetic patients. The goal of this work was to assess usefulness of MPI among diabetic patients. This work includes 44 diabetic patients (22 women, 22 men), investigated by stress MPI in nuclear medicine department of Ibn Rochd UH of Casablanca. The studied parameters concerned: age, antecedents of CAD, risk factors of CAD associated to diabetes, duration of the diabetes, diabetes complications, diabetes treatment, indication of MPI, presence or not of anomaly on the ECG performed at rest, existence or not of typical or atypical clinical signs of CAD, investigations and therapy prescribed as well as the occurrence or not of cardiac event during monitoring after MPI. Results of MPI have been compared to clinical, therapeutic and monitoring data of patients. Mean age of patients was 55 years (39 to 75 years), mean diabetes duration was 8.6 years (1 to 30 years), at least one diabetes complication has been noted in 18 patients. The most frequent complication was diabetic retinopathy. MPI has been achieved for diagnosis of ischemia in 37 patients and assessment of anti-ischemic treatment in 7 cases. Treadmill exercise has been achieved in 34 cases and a pharmacological stress in 10 others. During follow-up, which was between 1 and 36 months (mean: 14.9 months), 6 cardiac events occurred among the 44 patients. Patients with abnormal findings at stress MPI had two cardiovascular risk factors or more associated to diabetes (91.3% vs. 9.5% among patients having normal findings, P < 0.001) and had diabetic retinopathy more often (56.5% vs. 9.5% among patients with normal findings, P < 0.001). Cardiac events were more frequent among men (100% vs. 43.2% of patients who did not have a coronary event, P < 0.01). Patients with stress MPI showing ischemia in 3/17 segments or more have presented a cardiac event more often during the follow-up (4/12 Vs 2/32 among patients with normal MPI or defect in less than 3/17 segments, P < 0.01). In this series, coronary artery disease was found more frequently among patients having more than 2 cardiovascular risk factors. In addition, risk of cardiac event seems related to extent of uptake decrease.     

线粒体分裂蛋白抑制剂在大鼠脑缺血再灌注损伤中的作用及其机制

目的:观察线粒体分裂蛋白抑制剂在大鼠脑缺血再灌注损伤中的作用,并初步探讨其在线粒体凋亡途径中的作用机制.方法:雄性Wistar大鼠48只,体重250～300 g,随机分为三组(n=16):假手术组(Sham组)、脑缺血再灌注组(I/R组)和mdivi-1预处理组(mdivi-1组),线栓法建立大鼠大脑中动脉闭塞(MCAO)模型,缺血2小时,再灌注24小时后应用流式细胞术检测神经元凋亡;Western blot法检测Cyt C蛋白的表达;RT-PCR法检测Cyt C mRNA的表达.结果:与Sham组比较,I/R组神经细胞凋亡率与CytC蛋白以及mRNA表达水平显著升高(P＜0.01).应用mdivi-1预处理后细胞凋亡率与CytC蛋白以及mRNA表达水平明显降低(P＜0.01).结论:线粒体分裂蛋白抑制剂可以明显减轻脑缺血再灌注损伤,其作用机制可能通过阻断线粒体-细胞色素C途径来抑制细胞凋亡.     

异丙酚和氯胺酮对大鼠离体缺血再灌注损伤心肌脂质过氧化的影响

目的：比较异丙酚和氯胺酮对大鼠离体缺血再灌注损伤心肌脂质过氧化的影响。方法：成年Wistar大鼠18只,雌雄不拘。体重240-300g,随机分为3组（T1=6）：心肌缺血再灌注损伤组（I／R组）,异丙酚组（P组）,氯胺酮组（K组）。采用Langendorff灌装置建立离体心脏缺血再灌注模型,将心脏连接至Langendorff逆灌装置,3组均以K-H液平衡灌注10min后,再分别以K．H液、含30μmol/L。异丙酚的K-H液、含10μmol-L-1氯胺酮的K-H液灌注10min,然后全心停灌25min,再分别以停灌前相同的灌注液恢复灌注30min。留取冠脉流出液测定总LDH活性;灌注末取左室心肌组织置于2．5％的戊二醛固定,观察心肌的超微结构;心尖部心肌组织留待检测8-异前列腺素和SOD活性。结果：与I／R组比较,P组8-异前列腺素含量降低,SOD活性升高,LDH活性降低（P〈0．05）;K组8-异前列腺素含量,SOD及LDH活性均无统计学意义（P〉0．05）;与P组比较,K组8-异前列腺素含量升高,SOD及LDH活性降低（P〈0．05）;P组心肌超微结构损伤较m组和K组也明显改善。结论：异丙酚可显著减轻心肌缺血再灌注损伤大鼠的脂质过氧化和心肌缺血再灌注损伤,而氯胺酮没有抗心肌缺血再灌注损伤心肌脂质过氧化的作用。     

Apigenin-7-O-β-D-(-6'-p-coumaroyl)-Glucopyranoside Treatment Elicits Neuroprotective Effect against Experimental Ischemic Stroke

Stroke is the major cause of permanent disability and mortality in China. Apigenin-7-O-β-D-(-6''''-p-coumaroyl)-glucopyranoside (APG) is a glycoside subtype of apigenin and has the antioxidant activity; however, whether and how it plays a neuroprotective role following cerebral ischemia remains unknown. In present study, we adopted the oxygen glucose/reperfusion model in PC12 cells, bilateral common carotid artery occlusion model in C57B6 mice and middle cerebral artery occlusion model in SD rats to observe the therapeutic effects of APG on ischemic stroke. We also discussed the underlying mechanism. Treatment with 0.4 μg/ml or 0.8 μg/ml APG promoted cell viability and proliferation, reduced LDH release and apoptotic cell death levels in PC12 cells. Treatment with 50 mg/kg or 100 mg/kg APG at 30 minutes after reperfusion improved neurological outcomes in vivo, as demonstrated by elevation of neurological scores in both mice and rats. It also increased the number of survival neurons in mice and reduced infarct volume in rats. APG also increased the contents of Mn-SOD and the phosphorylation level of STAT3, elevated the antioxidant activity and reduced oxidative productions. These findings revealed a neuroprotective effect of APG, which possibly induced by the STAT3 phosphorylation-mediated Mn-SOD up-regulation.