瞬时受体电位通道高血压治疗的新靶点课件

,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,瞬时受体电位通道_高血压治疗的新靶点,瞬时受体电位通道_高血压治疗的新靶点,1,高血压,危险因素,CVD,事件,高血压是心血管事件链的重要环节,血脂异常,冠心病,糖尿病 肾脏损害,肥胖 脑卒中,代谢综合征,外周血管病,不良生活方式 心功能不全,高血压危险因素CVD事件高血压是心血管事件链的重要环节血脂异,2,高血压的非药物干预,限盐可致血压下降,3-5mmHg,减肥致血压下降个体差异大，荟萃分析肥胖者,2,年，体重下降,1kg,血压下降,0.5mmHg,Aucott L, et al. Hypertension, 2005,45:1035-1041,高血压的非药物干预限盐可致血压下降3-5mmHg, 减肥致血,3,高血压的药物治疗,高血压的药物治疗,4,高血压的药物治疗,(,Drugs related to RAAS),高血压的药物治疗 (Drugs related to RA,5,降压效应难于完全用药理机制解释,CCB,较少证据显示高血压时电压依赖钙通道表达异常,2. ARB,和,ACEI,较少证据显示高血压时组织与循环,RAS,异常，拮抗,RAS,与组织,ATR,、,AngII,改变不平行,3,.,受体阻断剂,降压机制至今仍不甚清楚,4.,噻嗪类利尿剂,难以证实低剂量的效应与利尿钠有关,降压效应难于完全用药理机制解释CCB,6,细胞钙是血管功能调控的重要信号分子钙信号调节异常是高血压血管阻力增高的重要特征,Hilgers RHP and Webb RC. Exp Biol Med, 2005,细胞钙是血管功能调控的重要信号分子钙信号调节异常是高血压血,7,Lifton RP, Cell, 2001 OShanghnessy KM, JCI, 2004,钠盐摄取是影响血压最重要的环节因素之一，,细胞钠水潴留对高血压发生有重要影响,Lifton RP, Cell, 2001 OShang,8,Cosens, D. J. & Manning, A. Abnormal electroretinogram from a,Drosophila,mutant.,Nature,224, 285-287 (1969),Drosophila melanogaster,mutant,WT,light,light,on,on,off,off,瞬时受体电位通道,(transient receptor potential channel,，,TRPC),Cosens, D. J. & Manning, A. Ab,9,一种新的非选择性阳离子通道家族，体内分布广泛，分不同的亚型,瞬时受体电位通道家族,(transient receptor potential channel,，,TRP Channel),Firth AL et al. / Biochimica et Biophysica Acta, 2007,Putney JW Pflugers Arch Eur J Physiol,2005,一种新的非选择性阳离子通道家族，体内分布广泛，分不同,10,瞬时受体电位通道,Transient receptor potential channels (TRPCs),A.L. Firth et al. / Biochimica et Biophysica Acta 1772 (2007),Putney JW Pflugers Arch Eur J Physiol,2005,451:29-34,兼有受体和离子通道的特征，介导钙和钠等阳离子内流，但,其在高血压中的作用尚不清楚。,瞬时受体电位通道 Transient receptor p,11,Distribution of TRP channels in vasculature,Distribution of TRP channels i,12,Possible function of TRPCs,in the vasculature,Cir Res, 2006,Possible function of TRPCs in,13,TRP,通道与疾病的联系,1.Physiological role of TRPC in blood pressure,2. Pathogenesis of TRPC in primary hypertension,3. Our work about TRPC,4. Clinical relevance of TRPCs Novel target ?,TRP通道与疾病的联系1.Physiological rol,14,TRPC6 in hypertension,Enhancement of receptor-operated cation current and TRPC6 expression in arterial smooth muscle cells of deoxycorticosterone acetate-salt hypertensive rats.,Young Min Baea,J of Hypertens,2007,25,:809817,TRPC6 in hypertensionEnhanceme,15,Role of TRPV1 in hypertension,Wang et al.,Hypertension,. 2006;47:609-614,Role of TRPV1 in hypertensi,16,Role of TRPM7 in hypertension,Touyz RM.,Am J Physiol,290: R73R78, 2006.,Role of TRPM7 in hypertensionT,17,高血压病人和,SHR,单核细胞,TRPC3,表达上调，其介导的钙内流增加,M TRPC1 TRPC3 TRPC4 TRPC5 TRPC6 GAPDH M,Fluorescence ratio,(arbitrary units),Liu DY,Zhu ZM. Am J Hypertens, 2005, 2008, J Hypertens, 2006, 2007,Blank TRPC1 TRPC3 TRPC4 TRPC5 TRPC6,高血压病人和SHR单核细胞TRPC3表达上调，其介导的钙内流,18,Role of TRPC3 in the pathogenesis of hypertension,Role of TRPC3 in the pathogene,19,Identification of TRPC3 in the vasculature,Liu, et al. Hypertension, 2009,Identification of TRPC3 in the,20,Increased expression of TRPC3 in aorta from SHR,Liu, et al. Hypertension, 2009,Increased expression of TRPC3,21,Effect of TRPC3 upregulation on angiotensin II -induced calcium increase in SHR,Liu, et al. Hypertension, 2009,Effect of TRPC3 upregulation o,22,Effect of TRPC3 gene knockdown on angiotensin II induced calcium increase in SHR,Liu, et al. Hypertension, 2009,Effect of TRPC3 gene knockdown,23,Angiotensin II increases TRPC3 in VSMC from SHR,Liu, et al. Hypertension, 2009,Angiotensin II increases TRPC3,24,Effect of CCB/SKF on Angiotensin II-induced aortic contraction and calcium increase in VSMC from SHR,Liu, et al. Hypertension, 2009,Effect of CCB/SKF on Angiotens,25,Long term administration of AT1R antagonist telmisartan but not of calcium channel blocker amlodipine reduces TRPC3 in vivo,Liu, et al. Hypertension, 2009,Long term administration of AT,26,Vasomotion occurs in arteries either spontaneously or in response to pressure, stretch or application of vasoconstrictor agonists, which is associated with slow oscillations of smooth muscle membrane potential and of intracellular calcium concentrations. Vasomotion may also be enhanced by oscillations of transplasmamembrane calcium influx. TRP channels have been described to play an important role for calcium influx.,TRPCs,Ca2+,Vasomotion occurs in arteries,27,What is pathophysiological relevance of vasomotion ?,In several experimental models of hypertension,an increased vasomotion of arteries had been described.,Lefer et al. observed enhanced vasomotion of cerebral arterioles in spontaneously hypertensive rats compared to normotensive rats (Lefer et al., 1990).,An increased vasomotion was observed in segments of posterior cerebral arteries and in mesenteric arteries from spontaneously hypertensive stroke-prone rats compared to Wistar-Kyoto rats(Osol Tsai et al., 1995).,Vasomotion of coronary artery causes cardiac ischemia,.,What is pathophysiological rel,28,Norepinephrine (NE) caused a rapid vasonconstriction and followed by synchronized oscillations of vascular tone (vasomotion) in mesenteric artery rings from SHR,Norepinephrine (NE) caused a r,29,Increased NE-induced vasomotion,in mesenteric artery rings from SHR,Increased NE-induced vasomotio,30,Immunohistochemistry shows TRPCs distribution in mesenteric arteries,Immunohistochemistry shows TRP,31,Increased expression of TRPC1, TRPC3, TRPC5 in mesenteric artery from SHR,Increased expression of TRPC1,32,Inhibition of TRPC significantly attenuates NE-induced vasomotion in SHR,Inhibition of TRPC significant,33,Inhibition of NE-induced vasomotion in mesenteric arteries from SHR by specific TRPC antibodies,TRPC1,Control,Control,TRPC3,Inhibition of NE-induced vasom,34,Specific antagonizing TRP Channel subtypes significantly reduced vasomotion,Specific antagonizing TRP Chan,35,Inhibition,of NE-induced calcium increase in mesenteric arteries from SHR by specific TRPC antibodies,Inhibition of NE-induced calci,36,Effects of ARB and CCB on vasomotion and systolic blood pressure in SHR,Ctr,Amlo,Telm,Cand,Effects of ARB and CCB on vaso,37,Effects of ARB and CCB on TRPCs expression of mesenteric artery,TRPC1,TRPC3,TRPC5,-actin,Ctr,Cand,Almo,Telm,Effects of ARB and CCB on TRP,38,Summary,Summary,39,TRP Channel: Novel Therapeutic Targets for Hypertension?,The present results point to the relevance of TRPC3 in the,pathogenesis of primary hypertension. As indicated by recent,literature, expression of several TRP channel subtypes may be,divergent and redundant in cardiovascular diseases. Moreover,TRP channels display diverse properties, localization, and,regulation as a result of their assembly into distinct homomeric and heteromeric channel complexes. However, TRP channels will be fascinating targets to elucidate novel pathogenic mechanisms in hypertension, and TRP channels will be new therapeutic targets for cure of hypertension.,TRP Channel: Novel Therapeutic,40,ACKNOWLEDGMENS,Center for Hypertension and Metabolic Diseases,Third Military Medical University, Chongqing,Ma Liqun, Liqun Ma, Zhidan Luo, Tingbing Cao, Dachun Yang, Shundao Ma, Zhencheng Yan, Lijuan Wang, Shanjun Zhu, Daoyan Liu,Med.Klinik, Charite Campus Benjamin Franklin, Berlin, Germany,Martin Tepel,of Funding,Natural Science Foundation of China No. 30470830,973 program No. 2006CB503804 and 2006CB503905,Acknowledgments,ACKNOWLEDGMENS,41,Thank you for your attention,Thank you for your attention,42,