Autoimmune activities have been implicated in the pathogenesis of hypertension.High levels of autoantibodies against the second extracellular loop of α1-adrenoceptor(α1-AR autoantibody,α1-AA) are found in patients ...Autoimmune activities have been implicated in the pathogenesis of hypertension.High levels of autoantibodies against the second extracellular loop of α1-adrenoceptor(α1-AR autoantibody,α1-AA) are found in patients with hypertension,and α1-AA could exert a α1-AR agonist-like vasoconstrictive effect.However,whether the vasoconstrictive effect of α1-AA is enhanced in hypertension is unknown.Using aortic rings of spontaneously hypertensive rats(SHR) and normotensive Wistar-Kyoto(WKY) rats,we observed the vasoconstrictive responses to α1-AA with phenylephrine(α1-AR agonist) as a positive control drug.Aortic nitrotyrosine levels were also measured by ELISA and immunohistochemistry.The results showed that the aortic constrictive responses to α1-AA and phenylephrine(both 1 nmol L-1-10 μmol L-1) were greater in SHR than in WKY rats.Endothelial denudation or L-NAME(a non-selective NOS inhibitor)(100 μmol L-1) increased α1-AA- or phenylephrine-induced vasoconstrictions both in SHR and WKY.However,selective iNOS inhibitor 1400W(10 μmol L-1) enhanced the α1-AA-induced aortic constriction in WKY,but not in SHR.The aortic nitrotyrosine level was significantly higher in SHR than WKY,as shown by both ELISA and immunohistochemistry.These results indicate that the vasoconstrictive response to α1-AA is enhanced in SHR,and this altered responsiveness is due to endothelial dysfunction and decreased NO bioavailability.The study suggests an important role of α1-AR autoimmunity in the pathogenesis and management of hypertension especially in those harboring high α1-AA levels.展开更多
Background Chronic heart failure （CHF） had been characterized as an activated sympathetic system leading to the alteration of adrenergic receptor （AR） levels in the heart. Thus far, not much research has been don...Background Chronic heart failure （CHF） had been characterized as an activated sympathetic system leading to the alteration of adrenergic receptor （AR） levels in the heart. Thus far, not much research has been done with regard to traditional Chinese medical treatment for CHF. We investigated the effect of Shexiangbaoxin pills （SXBXP） on the function of the heart and the expression of a1-AR and b-AR subtypes in the messenger RNA （mRNA） levels and protein levels of non-infarction left ventricular tissue from rats with CHF induced by myocardial infarction.Methods Models of CHF were established by left anterior descending coronary artery ligature. Fifty-four Wistar rats were randomly divided into five groups： normal control group （group A）, sham operation group （group B）, CHF model group （group C）, positive medicine control group （group D）, and small-dose SXBXP group （group E） and large-dose SXBXP group （group F）, deployed intragastrically. Cardiac function was examined by echocardiography before and after therapy; mRNA expressed levels were measured by semiquantitative reverse transcription polymerase chain reaction （RT-PCR） for b1-AR, b2-AR, b3-AR, a1A-AR, a1B-AR, and a1D-AR; protein levels were measured by Western blotting analysis for b1-AR, b2-AR, a1A-AR, a1B-AR, and a1D-AR in non-infarction left ventricular tissue.Results There was no significant difference in the left ventricular ejection fraction （LVEF） between groups A and B. Compared to group B, LVEF of groups C, D, E, and F were significantly decreased （P 〈0.01） before therapy. After therapy, compared to group C, LVEF of group F was significantly improved （P 〈0.05）. Compared to group B, b1-AR and a1B-AR expressed levels were markedly decreased （P 〈0.05）, a1A-AR and b3-AR were significantly increased （P 〈0.01） in group C, and in both mRNA and protein expressed levels b2-AR had no significant difference between groups B and C （P 〉0.05）. a1D-AR mRNA levels were unchanged in each展开更多
Rapid over-activation of β-adrenergic receptors (β-AR) following acute stress initiates cardiac inflammation and injury by activating interleukin-18 (IL-18),however,the process of inflammation cascades has not been ...Rapid over-activation of β-adrenergic receptors (β-AR) following acute stress initiates cardiac inflammation and injury by activating interleukin-18 (IL-18),however,the process of inflammation cascades has not been fully illustrated.The present study aimed to determine the mechanisms of cardiac inflammatory amplification following acute sympathetic activation.With bioinformatics analysis,galectin-3 was identified as a potential key downstream effector of β-AR and IL-18 activation.The serum level of galectin-3 was positively correlated with norepinephrine or IL-18 in patients with chest pain.In the heart of mice treated with β-AR agonist isoproterenol (ISO,5 mg kg^(-1)),galectin-3 expression was upregulated markedly later than IL-18 activation,and Nlrp3^(-/-)and Il18^(-/-)mice did not show ISO-induced galectin-3 upregulation.It was further revealed that cardiomyocyte-derived IL-18 induced galectin-3 expression in macrophages following ISO treatment.Moreover,galectin-3deficiency suppressed ISO-induced cardiac inflammation and fibrosis without blocking ISO-induced IL-18 increase.Treatment with a galectin-3 inhibitor,but not a β-blocker,one day after ISO treatment effectively attenuated cardiac inflammation and injury.In conclusion,galectin-3 is upregulated to exaggerate cardiac inflammation and injury following acute β-AR activation,a galectin-3 inhibitor effectively blocks cardiac injury one day after β-AR insult.展开更多
本文旨在探讨缺血预处理(ischemic preconditioning,IP)对缺血/再灌注(ischemia/reperfusion,I/R)损伤心脏的保护机制,从细胞和受体水平研究β2-肾上腺素受体(β2-adrenoreceptor,β2-AR)是否参与了IP对I/R损伤心脏的保护作用。Sprague-...本文旨在探讨缺血预处理(ischemic preconditioning,IP)对缺血/再灌注(ischemia/reperfusion,I/R)损伤心脏的保护机制,从细胞和受体水平研究β2-肾上腺素受体(β2-adrenoreceptor,β2-AR)是否参与了IP对I/R损伤心脏的保护作用。Sprague-Dawley大鼠随机分为单纯I/R组(对照组)、IP组、短暂异丙肾上腺素(isoproterenol,ISO)处理组、IP+ICI118551组、ISO+ICI118551组和ICI118551组。除对照组外,其它各组大鼠处理后均行缺血30min/复灌30min。记录心脏收缩期左心室内压上升的最大变化速率(+dp/dtmax)、舒张期左心室内压下降的最大变化速率(-dp/dtmax)及左心室内压差(difference of left ven-tricular pressure,ΔLVP,左心室收缩压-左心室舒张压)。测定冠状动脉流出液乳酸脱氢酶(lactate dehydrogenase,LDH)含量。进一步酶解分离心脏,获得单个心室肌细胞,测定其存活率和收缩功能。结果显示,IP和ISO组±dp/dtmax、ΔLVP较对照组增高;心肌细胞存活率和收缩幅度也显著升高;收缩时间(time-to-peak contraction,TTP)缩短;冠状动脉流出液LDH含量减少。选择性β2-AR拮抗剂ICI118551阻断IP和ISO的作用。各组间心肌细胞舒张50%时间(time-to-50%relaxation,R50)和舒张100%时间(time-to-100%relaxation,R100)均无明显差异。结果提示,β2-AR可能在IP对I/R损伤心脏的保护作用中发挥重要作用。展开更多
基金supported by the National Natural Science Foundation of China (81000107,30670835,81071072,31171088)the National Basic Research Program of China (2011CB933500)grants from Key Laboratory of Medical Electrophysiology of Sichuan Province (MEPSCKL2011-01)
文摘Autoimmune activities have been implicated in the pathogenesis of hypertension.High levels of autoantibodies against the second extracellular loop of α1-adrenoceptor(α1-AR autoantibody,α1-AA) are found in patients with hypertension,and α1-AA could exert a α1-AR agonist-like vasoconstrictive effect.However,whether the vasoconstrictive effect of α1-AA is enhanced in hypertension is unknown.Using aortic rings of spontaneously hypertensive rats(SHR) and normotensive Wistar-Kyoto(WKY) rats,we observed the vasoconstrictive responses to α1-AA with phenylephrine(α1-AR agonist) as a positive control drug.Aortic nitrotyrosine levels were also measured by ELISA and immunohistochemistry.The results showed that the aortic constrictive responses to α1-AA and phenylephrine(both 1 nmol L-1-10 μmol L-1) were greater in SHR than in WKY rats.Endothelial denudation or L-NAME(a non-selective NOS inhibitor)(100 μmol L-1) increased α1-AA- or phenylephrine-induced vasoconstrictions both in SHR and WKY.However,selective iNOS inhibitor 1400W(10 μmol L-1) enhanced the α1-AA-induced aortic constriction in WKY,but not in SHR.The aortic nitrotyrosine level was significantly higher in SHR than WKY,as shown by both ELISA and immunohistochemistry.These results indicate that the vasoconstrictive response to α1-AA is enhanced in SHR,and this altered responsiveness is due to endothelial dysfunction and decreased NO bioavailability.The study suggests an important role of α1-AR autoimmunity in the pathogenesis and management of hypertension especially in those harboring high α1-AA levels.
文摘Background Chronic heart failure （CHF） had been characterized as an activated sympathetic system leading to the alteration of adrenergic receptor （AR） levels in the heart. Thus far, not much research has been done with regard to traditional Chinese medical treatment for CHF. We investigated the effect of Shexiangbaoxin pills （SXBXP） on the function of the heart and the expression of a1-AR and b-AR subtypes in the messenger RNA （mRNA） levels and protein levels of non-infarction left ventricular tissue from rats with CHF induced by myocardial infarction.Methods Models of CHF were established by left anterior descending coronary artery ligature. Fifty-four Wistar rats were randomly divided into five groups： normal control group （group A）, sham operation group （group B）, CHF model group （group C）, positive medicine control group （group D）, and small-dose SXBXP group （group E） and large-dose SXBXP group （group F）, deployed intragastrically. Cardiac function was examined by echocardiography before and after therapy; mRNA expressed levels were measured by semiquantitative reverse transcription polymerase chain reaction （RT-PCR） for b1-AR, b2-AR, b3-AR, a1A-AR, a1B-AR, and a1D-AR; protein levels were measured by Western blotting analysis for b1-AR, b2-AR, a1A-AR, a1B-AR, and a1D-AR in non-infarction left ventricular tissue.Results There was no significant difference in the left ventricular ejection fraction （LVEF） between groups A and B. Compared to group B, LVEF of groups C, D, E, and F were significantly decreased （P 〈0.01） before therapy. After therapy, compared to group C, LVEF of group F was significantly improved （P 〈0.05）. Compared to group B, b1-AR and a1B-AR expressed levels were markedly decreased （P 〈0.05）, a1A-AR and b3-AR were significantly increased （P 〈0.01） in group C, and in both mRNA and protein expressed levels b2-AR had no significant difference between groups B and C （P 〉0.05）. a1D-AR mRNA levels were unchanged in each
基金supported by the National Key R&D Program of China (2021YFF0501401)the National Natural Science Foundation of China (82030072)+5 种基金the Michigan Medicine-PKUHSC Joint Institute for Translational and Clinical Research (BMU2019JI007)the Fundamental Research Funds for the Central Universitiesthe National Natural Science Foundation of China (81830009, 81822003)the Beijing Municipal Natural Science Foundation (7191013)the Key Clinical Projects of Peking University Third Hospital (BYSYZD2019022)CAMS Innovation Fund for Medical Sciences to (2021-I2M-5-003)。
文摘Rapid over-activation of β-adrenergic receptors (β-AR) following acute stress initiates cardiac inflammation and injury by activating interleukin-18 (IL-18),however,the process of inflammation cascades has not been fully illustrated.The present study aimed to determine the mechanisms of cardiac inflammatory amplification following acute sympathetic activation.With bioinformatics analysis,galectin-3 was identified as a potential key downstream effector of β-AR and IL-18 activation.The serum level of galectin-3 was positively correlated with norepinephrine or IL-18 in patients with chest pain.In the heart of mice treated with β-AR agonist isoproterenol (ISO,5 mg kg^(-1)),galectin-3 expression was upregulated markedly later than IL-18 activation,and Nlrp3^(-/-)and Il18^(-/-)mice did not show ISO-induced galectin-3 upregulation.It was further revealed that cardiomyocyte-derived IL-18 induced galectin-3 expression in macrophages following ISO treatment.Moreover,galectin-3deficiency suppressed ISO-induced cardiac inflammation and fibrosis without blocking ISO-induced IL-18 increase.Treatment with a galectin-3 inhibitor,but not a β-blocker,one day after ISO treatment effectively attenuated cardiac inflammation and injury.In conclusion,galectin-3 is upregulated to exaggerate cardiac inflammation and injury following acute β-AR activation,a galectin-3 inhibitor effectively blocks cardiac injury one day after β-AR insult.
基金This work was supported by the Natural Science Foundation of Jiangsu Province(No.04KJA180110),Social Development Foundation of Nantong(No.S40057,S5040),the National Natural Science Foundation of China(No. 30370462),the NSFC-RGC Joint Research Scheme of the National Natural Science Foundation of China(No.30318004)and RFDP of the State Educational Ministry of China(No. 20050284025).
基金the Social Development Program of Xuzhou Municipality (No. 58)
文摘本文旨在探讨缺血预处理(ischemic preconditioning,IP)对缺血/再灌注(ischemia/reperfusion,I/R)损伤心脏的保护机制,从细胞和受体水平研究β2-肾上腺素受体(β2-adrenoreceptor,β2-AR)是否参与了IP对I/R损伤心脏的保护作用。Sprague-Dawley大鼠随机分为单纯I/R组(对照组)、IP组、短暂异丙肾上腺素(isoproterenol,ISO)处理组、IP+ICI118551组、ISO+ICI118551组和ICI118551组。除对照组外,其它各组大鼠处理后均行缺血30min/复灌30min。记录心脏收缩期左心室内压上升的最大变化速率(+dp/dtmax)、舒张期左心室内压下降的最大变化速率(-dp/dtmax)及左心室内压差(difference of left ven-tricular pressure,ΔLVP,左心室收缩压-左心室舒张压)。测定冠状动脉流出液乳酸脱氢酶(lactate dehydrogenase,LDH)含量。进一步酶解分离心脏,获得单个心室肌细胞,测定其存活率和收缩功能。结果显示,IP和ISO组±dp/dtmax、ΔLVP较对照组增高;心肌细胞存活率和收缩幅度也显著升高;收缩时间(time-to-peak contraction,TTP)缩短;冠状动脉流出液LDH含量减少。选择性β2-AR拮抗剂ICI118551阻断IP和ISO的作用。各组间心肌细胞舒张50%时间(time-to-50%relaxation,R50)和舒张100%时间(time-to-100%relaxation,R100)均无明显差异。结果提示,β2-AR可能在IP对I/R损伤心脏的保护作用中发挥重要作用。
