Neurotoxic astrocytes are a promising therapeutic target for the attenuation of cerebral ischemia/reperfusion injury.Low-density lipoprotein receptor,a classic cholesterol regulatory receptor,has been found to inhibit...Neurotoxic astrocytes are a promising therapeutic target for the attenuation of cerebral ischemia/reperfusion injury.Low-density lipoprotein receptor,a classic cholesterol regulatory receptor,has been found to inhibit NLR family pyrin domain containing protein 3(NLRP3)inflammasome activation in neurons following ischemic stroke and to suppress the activation of microglia and astrocytes in individuals with Alzheimer’s disease.However,little is known about the effects of low-density lipoprotein receptor on astrocytic activation in ischemic stroke.To address this issue in the present study,we examined the mechanisms by which low-density lipoprotein receptor regulates astrocytic polarization in ischemic stroke models.First,we examined low-density lipoprotein receptor expression in astrocytes via immunofluorescence staining and western blotting analysis.We observed significant downregulation of low-density lipoprotein receptor following middle cerebral artery occlusion reperfusion and oxygen-glucose deprivation/reoxygenation.Second,we induced the astrocyte-specific overexpression of low-density lipoprotein receptor using astrocyte-specific adeno-associated virus.Low-density lipoprotein receptor overexpression in astrocytes improved neurological outcomes in middle cerebral artery occlusion mice and reversed neurotoxic astrocytes to create a neuroprotective phenotype.Finally,we found that the overexpression of low-density lipoprotein receptor inhibited NLRP3 inflammasome activation in oxygen-glucose deprivation/reoxygenation injured astrocytes and that the addition of nigericin,an NLRP3 agonist,restored the neurotoxic astrocyte phenotype.These findings suggest that low-density lipoprotein receptor could inhibit the NLRP3-meidiated neurotoxic polarization of astrocytes and that increasing low-density lipoprotein receptor in astrocytes might represent a novel strategy for treating cerebral ischemic stroke.展开更多
目的通过研究原发性高血压(EH)患者的血清Lp(a)、Lp-PLA2水平与血压变异性(BPV)的特征,进一步探讨EH患者血清中Lp(a)和Lp-PLA2水平与BPV之间的关系。方法选取2022年9月至2023年9月于内蒙古自治区人民医院门诊及住院诊疗的EH患者240例。...目的通过研究原发性高血压(EH)患者的血清Lp(a)、Lp-PLA2水平与血压变异性(BPV)的特征,进一步探讨EH患者血清中Lp(a)和Lp-PLA2水平与BPV之间的关系。方法选取2022年9月至2023年9月于内蒙古自治区人民医院门诊及住院诊疗的EH患者240例。将患者分为A组:Lp(a)、Lp-PLA2均正常,115例;B组:仅Lp(a)升高,48例;C组:仅Lp-PLA2升高,42例;D组:Lp(a)、Lp-PLA2均升高,35例。探索Lp(a)和Lp-PLA2水平与血压变异性之间的相关性。结果B组各时段变异系数(CV)均高于A组(P<0.05);C组24 h SBPCV、24 h DBP CV、nSBP CV、dDBP CV、dSBP CV高于A组(P<0.05);D组各时段CV均高于A组(P<0.05)。Lp(a)、Lp-PLA2与BPV呈正相关(rs>0,P<0.05)。B组、C组以及D组的Lp(a)、Lp-PLA2和24 h SBP CV、24 h DBP CV间均呈显著正相关关系(rs>0,P<0.05)。结论EH患者血清Lp(a)、Lp-PLA2水平与BPV呈正相关,且血清Lp(a)、Lp-PLA2均升高的患者BPV也升高。展开更多
Lipoprotein（a） [Lp（a）] is composed of a low density lipoprotein（LDL）-like particle to which apolipoprotein（a）[apo（a）] is linked by a single disulfide bridge. Lp（a） is considered a causal risk factor for is...Lipoprotein（a） [Lp（a）] is composed of a low density lipoprotein（LDL）-like particle to which apolipoprotein（a）[apo（a）] is linked by a single disulfide bridge. Lp（a） is considered a causal risk factor for ischemic cardiovascular disease（CVD） and calcific aortic valve stenosis（CAVS）. The evidence for a causal role of Lp（a） in CVD and CAVS is based on data from large epidemiological databases, mendelian randomization studies, and genome-wide association studies. Despite the well-established role of Lp（a） as a causal risk factor for CVD and CAVS, the underlying mechanisms are not well understood. A key role in the Lp（a） functionality may be played by its oxidized phospholipids（OxPL） content. Importantly, most of circulating OxPL are associated with Lp（a）; however, the underlying mechanisms leading to this preferential sequestration of OxPL on Lp（a） over the other lipoproteins,are mostly unknown. Several studies support the hypothesis that the risk of Lp（a） is primarily driven by its OxPL content.An important role in Lp（a） functionality may be played by the lipoprotein-associated phospholipase A_2（Lp-PLA_2）,an enzyme that catalyzes the degradation of OxPL and is bound to plasma lipoproteins including Lp（a）. The present review article discusses new data on the pathophysiological role of Lp（a） and particularly focuses on the functional role of OxPL and Lp-PLA_2 associated with Lp（a）.展开更多
基金supported by the National Natural Science Foundation of China,No.82201460(to YH)Nanjing Medical University Science and Technology Development Fund,No.NMUB20210202(to YH).
文摘Neurotoxic astrocytes are a promising therapeutic target for the attenuation of cerebral ischemia/reperfusion injury.Low-density lipoprotein receptor,a classic cholesterol regulatory receptor,has been found to inhibit NLR family pyrin domain containing protein 3(NLRP3)inflammasome activation in neurons following ischemic stroke and to suppress the activation of microglia and astrocytes in individuals with Alzheimer’s disease.However,little is known about the effects of low-density lipoprotein receptor on astrocytic activation in ischemic stroke.To address this issue in the present study,we examined the mechanisms by which low-density lipoprotein receptor regulates astrocytic polarization in ischemic stroke models.First,we examined low-density lipoprotein receptor expression in astrocytes via immunofluorescence staining and western blotting analysis.We observed significant downregulation of low-density lipoprotein receptor following middle cerebral artery occlusion reperfusion and oxygen-glucose deprivation/reoxygenation.Second,we induced the astrocyte-specific overexpression of low-density lipoprotein receptor using astrocyte-specific adeno-associated virus.Low-density lipoprotein receptor overexpression in astrocytes improved neurological outcomes in middle cerebral artery occlusion mice and reversed neurotoxic astrocytes to create a neuroprotective phenotype.Finally,we found that the overexpression of low-density lipoprotein receptor inhibited NLRP3 inflammasome activation in oxygen-glucose deprivation/reoxygenation injured astrocytes and that the addition of nigericin,an NLRP3 agonist,restored the neurotoxic astrocyte phenotype.These findings suggest that low-density lipoprotein receptor could inhibit the NLRP3-meidiated neurotoxic polarization of astrocytes and that increasing low-density lipoprotein receptor in astrocytes might represent a novel strategy for treating cerebral ischemic stroke.
文摘目的通过研究原发性高血压(EH)患者的血清Lp(a)、Lp-PLA2水平与血压变异性(BPV)的特征,进一步探讨EH患者血清中Lp(a)和Lp-PLA2水平与BPV之间的关系。方法选取2022年9月至2023年9月于内蒙古自治区人民医院门诊及住院诊疗的EH患者240例。将患者分为A组:Lp(a)、Lp-PLA2均正常,115例;B组:仅Lp(a)升高,48例;C组:仅Lp-PLA2升高,42例;D组:Lp(a)、Lp-PLA2均升高,35例。探索Lp(a)和Lp-PLA2水平与血压变异性之间的相关性。结果B组各时段变异系数(CV)均高于A组(P<0.05);C组24 h SBPCV、24 h DBP CV、nSBP CV、dDBP CV、dSBP CV高于A组(P<0.05);D组各时段CV均高于A组(P<0.05)。Lp(a)、Lp-PLA2与BPV呈正相关(rs>0,P<0.05)。B组、C组以及D组的Lp(a)、Lp-PLA2和24 h SBP CV、24 h DBP CV间均呈显著正相关关系(rs>0,P<0.05)。结论EH患者血清Lp(a)、Lp-PLA2水平与BPV呈正相关,且血清Lp(a)、Lp-PLA2均升高的患者BPV也升高。
文摘Lipoprotein（a） [Lp（a）] is composed of a low density lipoprotein（LDL）-like particle to which apolipoprotein（a）[apo（a）] is linked by a single disulfide bridge. Lp（a） is considered a causal risk factor for ischemic cardiovascular disease（CVD） and calcific aortic valve stenosis（CAVS）. The evidence for a causal role of Lp（a） in CVD and CAVS is based on data from large epidemiological databases, mendelian randomization studies, and genome-wide association studies. Despite the well-established role of Lp（a） as a causal risk factor for CVD and CAVS, the underlying mechanisms are not well understood. A key role in the Lp（a） functionality may be played by its oxidized phospholipids（OxPL） content. Importantly, most of circulating OxPL are associated with Lp（a）; however, the underlying mechanisms leading to this preferential sequestration of OxPL on Lp（a） over the other lipoproteins,are mostly unknown. Several studies support the hypothesis that the risk of Lp（a） is primarily driven by its OxPL content.An important role in Lp（a） functionality may be played by the lipoprotein-associated phospholipase A_2（Lp-PLA_2）,an enzyme that catalyzes the degradation of OxPL and is bound to plasma lipoproteins including Lp（a）. The present review article discusses new data on the pathophysiological role of Lp（a） and particularly focuses on the functional role of OxPL and Lp-PLA_2 associated with Lp（a）.
