OBJECTIVE The Ca2+-activated Cl-channel(Ca CC)plays a crucial role in various physiological functions.Recent evidences suggest TMEM16A encodes CaC C in various cells,including endothelial cells.However,the role of TME...OBJECTIVE The Ca2+-activated Cl-channel(Ca CC)plays a crucial role in various physiological functions.Recent evidences suggest TMEM16A encodes CaC C in various cells,including endothelial cells.However,the role of TMEM16A in the vascular endothelial dysfunction in hypertension is unclear.METHODS In the study,RT-PCR,Western blotting,co-immunopricipitation,confocal imaging,patch-clamp,and endothelial-specific TMEM16A transgenic and knockout mice were employed.RESULTS We found that TMEM16A was expressed abundantly and functioned as Ca CC in endothelial cells.AngiotensinⅡ(AngⅡ)induced endothelial dysfunction with an increase in TMEM16A expression,which was alleviated by TMEM16A inhibitor.Further studies revealed that TMEM16A endothelial-specific knockout significantly lowered the blood pressure and ameliorated endothelial dysfunction in AngⅡ-induced hypertension,whereas,TMEM16A endothelial-specific overexpression showed the opposite effects.These results were related to the increased reactive oxygen species(ROS)generation,NADPH oxidase activation,and Nox2,p22phox expression facilitated by TMEM16A upon AngⅡ-induced hypertensive challenges.Moreover,TMEM16A directly interacted with Nox2 monomer and reduced the degradation of Nox2 through the proteasome-dependent endoplasmic recticulum-associated degradation pathway.TMEM16A also potentiated the translocation of p47phox and p67phox from cytosol to cell membrane and the subsequent interaction with Nox2.CONCLUSION Our results demonstrated that TMEM16A,as Ca CC,is a positive regulator of ROS generation via upregulating the activation of Nox2 NADPH oxidase in the vascular endothelium,and therefore facilitates endothelial dysfunction and hypertension.Modification of TMEM16A may be a novel therapeutic strategy for endothelial dysfunction-associated cardiovascular diseases.展开更多
目的:观察平肝降压汤联合辰时百会透刺治疗1、2级原发性高血压(EH)的临床疗效。方法:1、2级EH患者150例按照随机数字表法分为研究组和对照组,每组75例。对照组予以中药平肝降压汤口服,每日1剂,治疗8周;研究组予以平肝降压汤联合辰时百...目的:观察平肝降压汤联合辰时百会透刺治疗1、2级原发性高血压(EH)的临床疗效。方法:1、2级EH患者150例按照随机数字表法分为研究组和对照组,每组75例。对照组予以中药平肝降压汤口服,每日1剂,治疗8周;研究组予以平肝降压汤联合辰时百会透刺治疗,每次留针30 min,每日1次,每周6次,治疗8周。比较两组治疗前后中医证候评分、24 h平均收缩压(24 h ASBP)、24 h平均舒张压(24 h ADBP)、24 h平均脉压差(24 h PP)、晨峰血压(MBPS)、24 h SBP变异性(24 h SBPV)、24 h DBP变异性(24 h DBPV)、血清5-羟色胺(5-HT)和褪黑素(MT)含量的变化以及临床疗效。结果:治疗后两组头痛、眩晕、腰酸、膝软、耳鸣评分及24 h ASBP、24 h ADBP、24 h PP、MBPS、24 h SBPV、24 h DBPV均较治疗前降低(P<0.01),且研究组均低于对照组(P<0.01)。两组血清MT水平较治疗前升高(P<0.01),5-HT水平较治疗前降低(P<0.01)。研究组血清MT含量高于对照组(P<0.01),血清5-HT含量低于对照组(P<0.01)。研究组总有效率为93.3%(70/75)高于对照组的76.0%(57/75,P<0.01)。结论:平肝降压汤联合辰时百会透刺可调节血清MT、5-HT水平,有效降低血压,改善血压变异性,控制晨峰血压,治疗1、2级EH效果显著。展开更多
基金The project supported by National Natural Science Foundation of China(81230082,81302771,81525025,81573422,81500226)Natural Science Foundation of Guangdong Province(2014A030313087)by Science and Technology program of Guangzhou City(201607010255)
文摘OBJECTIVE The Ca2+-activated Cl-channel(Ca CC)plays a crucial role in various physiological functions.Recent evidences suggest TMEM16A encodes CaC C in various cells,including endothelial cells.However,the role of TMEM16A in the vascular endothelial dysfunction in hypertension is unclear.METHODS In the study,RT-PCR,Western blotting,co-immunopricipitation,confocal imaging,patch-clamp,and endothelial-specific TMEM16A transgenic and knockout mice were employed.RESULTS We found that TMEM16A was expressed abundantly and functioned as Ca CC in endothelial cells.AngiotensinⅡ(AngⅡ)induced endothelial dysfunction with an increase in TMEM16A expression,which was alleviated by TMEM16A inhibitor.Further studies revealed that TMEM16A endothelial-specific knockout significantly lowered the blood pressure and ameliorated endothelial dysfunction in AngⅡ-induced hypertension,whereas,TMEM16A endothelial-specific overexpression showed the opposite effects.These results were related to the increased reactive oxygen species(ROS)generation,NADPH oxidase activation,and Nox2,p22phox expression facilitated by TMEM16A upon AngⅡ-induced hypertensive challenges.Moreover,TMEM16A directly interacted with Nox2 monomer and reduced the degradation of Nox2 through the proteasome-dependent endoplasmic recticulum-associated degradation pathway.TMEM16A also potentiated the translocation of p47phox and p67phox from cytosol to cell membrane and the subsequent interaction with Nox2.CONCLUSION Our results demonstrated that TMEM16A,as Ca CC,is a positive regulator of ROS generation via upregulating the activation of Nox2 NADPH oxidase in the vascular endothelium,and therefore facilitates endothelial dysfunction and hypertension.Modification of TMEM16A may be a novel therapeutic strategy for endothelial dysfunction-associated cardiovascular diseases.
文摘目的:观察平肝降压汤联合辰时百会透刺治疗1、2级原发性高血压(EH)的临床疗效。方法:1、2级EH患者150例按照随机数字表法分为研究组和对照组,每组75例。对照组予以中药平肝降压汤口服,每日1剂,治疗8周;研究组予以平肝降压汤联合辰时百会透刺治疗,每次留针30 min,每日1次,每周6次,治疗8周。比较两组治疗前后中医证候评分、24 h平均收缩压(24 h ASBP)、24 h平均舒张压(24 h ADBP)、24 h平均脉压差(24 h PP)、晨峰血压(MBPS)、24 h SBP变异性(24 h SBPV)、24 h DBP变异性(24 h DBPV)、血清5-羟色胺(5-HT)和褪黑素(MT)含量的变化以及临床疗效。结果:治疗后两组头痛、眩晕、腰酸、膝软、耳鸣评分及24 h ASBP、24 h ADBP、24 h PP、MBPS、24 h SBPV、24 h DBPV均较治疗前降低(P<0.01),且研究组均低于对照组(P<0.01)。两组血清MT水平较治疗前升高(P<0.01),5-HT水平较治疗前降低(P<0.01)。研究组血清MT含量高于对照组(P<0.01),血清5-HT含量低于对照组(P<0.01)。研究组总有效率为93.3%(70/75)高于对照组的76.0%(57/75,P<0.01)。结论:平肝降压汤联合辰时百会透刺可调节血清MT、5-HT水平,有效降低血压,改善血压变异性,控制晨峰血压,治疗1、2级EH效果显著。
