亲代自发性高血压大鼠给予肾素血管紧张素阻断剂对子代心脏及血管的影响
摘要
目的
研究亲代自发性高血压大鼠给予给肾素血管紧张素阻断剂后对子代大鼠血压、心脏、血管的影响，以及血管紧张素受体（AngII type1b receptors，AT1b）和血管紧张素受体相关蛋白(Angiotensin receptor-associated protein，ATRAP)在上述过程中的作用。
方法
1健康SHR数对，亲代子代分别给予卡托普利或氯沙坦干预，观察子代血压、左心室重量指数、肠系膜三级动脉腔壁比、胸主动脉及肠系膜三级动脉的收缩功能以及内皮依赖性非内皮依赖性舒张功能。
2各实验组QRT-PCR检测子代大鼠心脏AT1b及ATRAP基因mRNA表达和western blot检测AT1，ATRAP蛋白水平的表达，以及焦磷酸测序心脏AT1b及ATRAP基因启动子区甲基化程度。
3体外培养心肌细胞，给予血管紧张素Ⅱ (100nmol/l)及卡托普利（10-9-10-5mmol/l）或氯沙坦（10-9-10-5mmol/l）同时干预，QRT-PCR检测AT1bmRNA、ATRAP mRNA表达, western blot检测AT1，ATRAP蛋白的表达，以及焦磷酸测序检测AT1b及ATRAP基因启动子区甲基化程度。
结果
1亲代SHR给予卡托普利、氯沙坦干预后，子代血压较SHR后代低（P<0.01）；左心室重量指数降低（P<0.01），肠系膜三级动脉动脉腔壁比降低（P<0.01）；胸主动脉及肠系膜三级动脉内皮依赖性舒张功能及非内皮舒张舒张功能有所提高（P<0.01）。
2亲代SHR给予卡托普利、氯沙坦干预后，子代在8周龄、16周龄时心脏AT1bmRNA及AT1蛋白有不同程度的下降（P<0.01）；ATRAP mRNA及蛋白有不同程度的上升（P<0.01）。
3亲代SHR给予卡托普利、氯沙坦干预后，子代在8周龄、16周龄时心脏ATRAP基因启动子区域甲基化程度有不同程度下降（P<0.01）。
4体外培养心肌细胞，给予ANGⅡ（100nmol/l）及10-5、10-6mmol/l卡托普利和氯沙坦时, AT1b mRNA及AT1蛋白表达有所减少（P<0.01）；ATRAP mRNA及蛋白表达有所增加（P<0.01）。
5体外培养心肌细胞，给予ANGⅡ（100nmol/l）及10-5、10-6mmol/l卡托普利和氯沙坦时, ATRAP基因启动子区域甲基化程度有所降低（P<0.01）。
结论
1亲代SHR给予卡托普利及氯沙坦治疗后，可以改善子代的血压，心脏和血管结构和功能。
2围生期治疗及长期的治疗可以改善子代大鼠胸主动脉和肠系膜动脉的内依赖性舒张功能及非内皮依赖性舒张功能
3亲代SHR给予卡托普利及氯沙坦治疗后，子代出现的血压和器官结构功能的改善，可能与AT1b表达减少和ATRAP表达增加有关。
4亲代SHR给予卡托普利及氯沙坦治疗后，出现ATRAP表达增加可能与其启动子区域的甲基化程度改变有关。
5围产期母体内环境对子代血压的形成以及心血管功能有较大影响。
Objective
To study the influence of renin-angiotensin blockers given during pregnantstages on the structural and functional changes of heart and artery in adult offspringrats.
Methods
Spontaneously hypertensive rats were fed with captopril or losartan throughoutpregnancy and or weaning, whose offspring were fed with captopril or with losartanentil16weeks old. Blood pressure, left ventricular mass index, wall to lumen arearatios(WPL) of mesenteric artery(3rd grade branch), endothelium-dependentvasodilation and endothelium-independent vasodilation of thoracic aorta andmesenteric artery(3rd grade branch) were determined in8and16-week-old offspringof captopril treated SHR or losartan treated SHR, which raised with captopril(F1CF1C)or with losartan(F1LF1L). The same detection indicators above were determined in8and16-week-old offspring of captopril treated SHR or losartan treated SHR whichwere raised without captopril (F1CF1N) or without losartan (F1LF1N) and in offspring ofSHR raised with captopril(F1NF1C) or with losartan(F1NF1L). The mRNA expression ofAT1gene and ATRAP gene in heart were detected in each group at8and16weeksold by QRT-PCR. DNA methylation was also detected by pyrosequencing. Theprotein expression of AT1and ATRAP in the male offsprings’ heart were detected ineach group by western blot. The immortalized cardiomyocyte cell line H9c2whichexpresses endogenous AT1and ATRAP was cultured with angiotensin II (100nmol/l)and10-9-10-5mmol/l captopril or losartan. The mRNA expression of AT1b gene andATRAP gene were detected in H9c2cell by QRT-PCR. DNA methylation wasdetected also by pyrosequencing. The protein expression of AT1and ATRAP weredetected in H9c2cell by western blot.
Result
1.F1CF1N, F1NF1C, F1CF1C,F1LF1N,F1NF1L, F1LF1Loffspring rats had lower blood pressure（P<0.01）, lower left ventricular weight index（P<0.01）, lower WPL（P<0.01）, higher endothelium-dependent vasodilation（P<0.01） and higherendothelium-independent vasodilation（P<0.01）.
2.AT1b mRNA and AT1protein of heart were lower in F1CF1N, F1NF1C, F1CF1C（P<0.01）,F1LF1N,F1NF1Land F1LF1L（P<0.01）at8weeks old.AT1b mRNA andAT1protein of heart were lower in F1NF1C, F1CF1C,F1NF1Land F1LF1L（P<0.01）at16weeks old. ATRAP mRNA and ATRAP of heart were higher in F1CF1N, F1NF1C, F1CF1C,F1LF1N,F1NF1L,F1LF1L（P<0.01）at8and16weeks old.
3.DNA methylation of ATRAP gene was decreased in F1CF1N, F1NF1C, F1CF1C,F1LF1N,F1NF1Land F1LF1L（P<0.01）.
4.10-9-10-5mmol/l captopril and losartan decreased AT1b mRNA（P<0.01） andthe protein expression of AT1（P<0.01） in H9c2cell.10-9-10-5mmol/l captopril andlosartan increased ATRAP mRNA（P<0.01）and ATRAP（P<0.01）in H9c2cell.
5.10-9-10-5mmol/l captopril and losartan decreased DNA methylation of ATRAPgene in H9c2cell（P<0.01）.
Conclusion
1. The treatment which parental SHR feed captopril or losartan andprehypertension treatment could improve blood pressure of SHR offspring. Structureand function of heart and artery were improved also by parental treatment.
2. The treatment which parental SHR feed captopril or losartan andprehypertension treatment could improve endothelium-dependent vasodilation andendothelium-independent vasodilation of offsprings’ thoracic aorta and mesentericartery(3rd grade branch).
3. The profit of structure and function of heart and artery might associate withAT1b and ATRAP.
4. DNA methylation of ATRAP gene might associate with the mRNA and proteinexpression of ATRAP.
5. Internal environment of perinatal had tremendous impact on the formation ofblood pressure and functional changes of cardiovascular system.
研究亲代自发性高血压大鼠给予给肾素血管紧张素阻断剂后对子代大鼠血压、心脏、血管的影响，以及血管紧张素受体（AngII type1b receptors，AT1b）和血管紧张素受体相关蛋白(Angiotensin receptor-associated protein，ATRAP)在上述过程中的作用。
方法
1健康SHR数对，亲代子代分别给予卡托普利或氯沙坦干预，观察子代血压、左心室重量指数、肠系膜三级动脉腔壁比、胸主动脉及肠系膜三级动脉的收缩功能以及内皮依赖性非内皮依赖性舒张功能。
2各实验组QRT-PCR检测子代大鼠心脏AT1b及ATRAP基因mRNA表达和western blot检测AT1，ATRAP蛋白水平的表达，以及焦磷酸测序心脏AT1b及ATRAP基因启动子区甲基化程度。
3体外培养心肌细胞，给予血管紧张素Ⅱ (100nmol/l)及卡托普利（10-9-10-5mmol/l）或氯沙坦（10-9-10-5mmol/l）同时干预，QRT-PCR检测AT1bmRNA、ATRAP mRNA表达, western blot检测AT1，ATRAP蛋白的表达，以及焦磷酸测序检测AT1b及ATRAP基因启动子区甲基化程度。
结果
1亲代SHR给予卡托普利、氯沙坦干预后，子代血压较SHR后代低（P<0.01）；左心室重量指数降低（P<0.01），肠系膜三级动脉动脉腔壁比降低（P<0.01）；胸主动脉及肠系膜三级动脉内皮依赖性舒张功能及非内皮舒张舒张功能有所提高（P<0.01）。
2亲代SHR给予卡托普利、氯沙坦干预后，子代在8周龄、16周龄时心脏AT1bmRNA及AT1蛋白有不同程度的下降（P<0.01）；ATRAP mRNA及蛋白有不同程度的上升（P<0.01）。
3亲代SHR给予卡托普利、氯沙坦干预后，子代在8周龄、16周龄时心脏ATRAP基因启动子区域甲基化程度有不同程度下降（P<0.01）。
4体外培养心肌细胞，给予ANGⅡ（100nmol/l）及10-5、10-6mmol/l卡托普利和氯沙坦时, AT1b mRNA及AT1蛋白表达有所减少（P<0.01）；ATRAP mRNA及蛋白表达有所增加（P<0.01）。
5体外培养心肌细胞，给予ANGⅡ（100nmol/l）及10-5、10-6mmol/l卡托普利和氯沙坦时, ATRAP基因启动子区域甲基化程度有所降低（P<0.01）。
结论
1亲代SHR给予卡托普利及氯沙坦治疗后，可以改善子代的血压，心脏和血管结构和功能。
2围生期治疗及长期的治疗可以改善子代大鼠胸主动脉和肠系膜动脉的内依赖性舒张功能及非内皮依赖性舒张功能
3亲代SHR给予卡托普利及氯沙坦治疗后，子代出现的血压和器官结构功能的改善，可能与AT1b表达减少和ATRAP表达增加有关。
4亲代SHR给予卡托普利及氯沙坦治疗后，出现ATRAP表达增加可能与其启动子区域的甲基化程度改变有关。
5围产期母体内环境对子代血压的形成以及心血管功能有较大影响。
Objective
To study the influence of renin-angiotensin blockers given during pregnantstages on the structural and functional changes of heart and artery in adult offspringrats.
Methods
Spontaneously hypertensive rats were fed with captopril or losartan throughoutpregnancy and or weaning, whose offspring were fed with captopril or with losartanentil16weeks old. Blood pressure, left ventricular mass index, wall to lumen arearatios(WPL) of mesenteric artery(3rd grade branch), endothelium-dependentvasodilation and endothelium-independent vasodilation of thoracic aorta andmesenteric artery(3rd grade branch) were determined in8and16-week-old offspringof captopril treated SHR or losartan treated SHR, which raised with captopril(F1CF1C)or with losartan(F1LF1L). The same detection indicators above were determined in8and16-week-old offspring of captopril treated SHR or losartan treated SHR whichwere raised without captopril (F1CF1N) or without losartan (F1LF1N) and in offspring ofSHR raised with captopril(F1NF1C) or with losartan(F1NF1L). The mRNA expression ofAT1gene and ATRAP gene in heart were detected in each group at8and16weeksold by QRT-PCR. DNA methylation was also detected by pyrosequencing. Theprotein expression of AT1and ATRAP in the male offsprings’ heart were detected ineach group by western blot. The immortalized cardiomyocyte cell line H9c2whichexpresses endogenous AT1and ATRAP was cultured with angiotensin II (100nmol/l)and10-9-10-5mmol/l captopril or losartan. The mRNA expression of AT1b gene andATRAP gene were detected in H9c2cell by QRT-PCR. DNA methylation wasdetected also by pyrosequencing. The protein expression of AT1and ATRAP weredetected in H9c2cell by western blot.
Result
1.F1CF1N, F1NF1C, F1CF1C,F1LF1N,F1NF1L, F1LF1Loffspring rats had lower blood pressure（P<0.01）, lower left ventricular weight index（P<0.01）, lower WPL（P<0.01）, higher endothelium-dependent vasodilation（P<0.01） and higherendothelium-independent vasodilation（P<0.01）.
2.AT1b mRNA and AT1protein of heart were lower in F1CF1N, F1NF1C, F1CF1C（P<0.01）,F1LF1N,F1NF1Land F1LF1L（P<0.01）at8weeks old.AT1b mRNA andAT1protein of heart were lower in F1NF1C, F1CF1C,F1NF1Land F1LF1L（P<0.01）at16weeks old. ATRAP mRNA and ATRAP of heart were higher in F1CF1N, F1NF1C, F1CF1C,F1LF1N,F1NF1L,F1LF1L（P<0.01）at8and16weeks old.
3.DNA methylation of ATRAP gene was decreased in F1CF1N, F1NF1C, F1CF1C,F1LF1N,F1NF1Land F1LF1L（P<0.01）.
4.10-9-10-5mmol/l captopril and losartan decreased AT1b mRNA（P<0.01） andthe protein expression of AT1（P<0.01） in H9c2cell.10-9-10-5mmol/l captopril andlosartan increased ATRAP mRNA（P<0.01）and ATRAP（P<0.01）in H9c2cell.
5.10-9-10-5mmol/l captopril and losartan decreased DNA methylation of ATRAPgene in H9c2cell（P<0.01）.
Conclusion
1. The treatment which parental SHR feed captopril or losartan andprehypertension treatment could improve blood pressure of SHR offspring. Structureand function of heart and artery were improved also by parental treatment.
2. The treatment which parental SHR feed captopril or losartan andprehypertension treatment could improve endothelium-dependent vasodilation andendothelium-independent vasodilation of offsprings’ thoracic aorta and mesentericartery(3rd grade branch).
3. The profit of structure and function of heart and artery might associate withAT1b and ATRAP.
4. DNA methylation of ATRAP gene might associate with the mRNA and proteinexpression of ATRAP.
5. Internal environment of perinatal had tremendous impact on the formation ofblood pressure and functional changes of cardiovascular system.
引文
[1]Kelly T N, Gu D F, Chen J, et al. Hypertension subtype and risk of cardiovasculardisease in Chinese adults. Circulation,2008,118(15):1558-1566.
[2]Gu D F, Reynolds K, Wu X G, et al. Prevalence, awareness, treatment and controlof hypertension in China. Hypertension,2002,40(6):920-927.
[3]林从容,吴可贵,谢良地,叶琼.血管紧张素Ⅱ一型受体基因A1166C多态性与高血压病的关系.高血压杂志,1999，09.7(3).225-228.
[4]刘晶晶，刑晓为等.β1肾上腺素能受体基因多态性及其甲基化修饰对美托洛尔降压疗效的影响[J].中国动脉硬化杂志，2008，Vol16,3:181-182.
[5]孙红梅,周奇文,吴丽芹.高血压病治疗费用的多因素分析[J].中国医疗前沿2009,15:116.
[6]Ding Y, Lv J, Mao C, Zhang H, Wang A, Zhu L, Zhu H, Xu Z. High-salt dietduring pregnancy and angiotensin-related cardiac changes. J Hypertens.2010Jun;28(6):1290-7. doi:10.1097.
[7] Kosaka S, Pelisch N, Rahman M, Nakano D, Hitomi H, Kobori H, Fukuoka N,Kobara H, Mori H, Masaki T, Cervenka L, Matsumura Y, Houchi H, NishiyamaA.Effects of Angiotensin II AT(1)-Receptor Blockade on High Fat Diet-InducedVascular Oxidative Stress and Endothelial Dysfunction in Dahl Salt-Sensitive Rats. JPharmacol Sci.2013Feb19;121(2):95-102.
[8] Seton-Rogers S. genetics: Methylation in the driver's seat? Nat Rev Cancer.2013Mar;13(3):149.
[9] Macones GA, Odibo A, Cahill A. Discussion:'Hypertension and antihypertensivesin pregnancy,' by Orbach H et al. Am J Obstet Gynecol.2013Feb18. doi:pii:S0002-9378(13)00219-6.
[10] Imran Khan, Vasia Dekou, Mark Hanson, Lucilla Poston and Paul Taylor.Predictive Adaptive Responses to Maternal High-Fat Diet Prevent EndothelialDysfunction but Not Hypertension in Adult Rat Offspring. Circulation2004,110:1097-1102.
[11]Funke-Kaiser H,Reichenberger F,Kopke K,et al.Differential binding oftranscription factor E2F-2to the endothelin-converting enzyme-1b promoter affectsblood pressure regulation.Hum Mol Genet,2003,12(4):423-433.
[12]Funke-Kaiser H,Thomas A,Bremer J,et al.Regulation of the major isoform ofhuman endothelin-converting enzyme-1by a strong housekeeping promotermodulated by polymorphic microsatellites.J Hypertens,2003,21(11):2111-2124.
[13]Bogdarina I G,King P J,Clark A J.Characterization of theangiotensin(AT1b)receptor promoter and its regulation by glucocorticoids.J MolEndocrinol,2009,43(2):73-80.
[14]Nuyt A M,Szyf M.Developmental programming through epigeneticchanges.Circ Res,2007,100(4):452-455.
[15]Yuan H,Huang Z J,Xing X W,et al.Inhibitors of DNA methyltransferase andhistone deacetylase regulate the expression ofβ1-adrenoceptor gene in myocardialcells.Cell Biol Int,2008,32.(3):S7-S8.
[16]Yuan H,Huang Z J,Yang G P,et al.Effects of polymorphism oftheβ1-adrenoreceptor and CYP2D6on the therapeutic effects of metoprolol.J Int MedRes,2008,36(6):1354-1362.
[17]Yuan H,Huang Z J,Liu J J,et al.Influence on metoprolol antihypertensive effectofβ1-adrenoceptor gene polymorphism and methylated modication.Cell BiolInt,2008,32(3):S7.
[18] Ding Y, Lv J, Mao C, Zhang H, Wang A, Zhu L, Zhu H, Xu Z High-salt dietduring pregnancy and angiotensin-related cardiac changes. J Hypertens.2010Jun;28(6):1290-7.
[19] Yutaka Tanakaa, Kouichi Tamuraa, Yuichi Koide, et al. The novel angiotensin IItype1receptor (AT1R)-associated protein ATRAP downregulates AT1R andameliorates cardiomyocyte hypertrophy. FEBS Letters579(2005)1579–1586.
[20]Sluimer JC, Gasc JM, Hamming I, et al. Angiotensin-converting enzyme2(ACE2)expression and activity in human carotid atherosclerotic lesions.JPathol,2008,215:273-9.
[21]Sierra A, Segura J, Banegas JR, et al. Clinical feature of8295patients withresistant hypertension classified on the basis of ambulatory blood pressure monitoring.Hypertension,2011,57:898-902.
[22] Calhoun DA, Jones D, Textor S et al. Resistant hyper-tension: diagnosisEvaluation and treatment: a sci-entific statement from the Am erican HeartAssociation Professional Education Committee of the Council for High BloodPressure Research. Circulation,2008117(25):510-526.
[23] Lowel H, Meisinger C, Heier M et al. Epidemiology of hypertension in Germany.Selected results of population-representative cross-sectional studies. Dtsch MedWochenschr,2006,131:2586-2591.
[24]Barker DJ. The fetal and infant origins of disease. Eur J Clin Invest25:457–463,1995.
[25] Lucas A. Role of nutritional programming in determining adult morbidity. ArchDis Childhood1994;71:288–290,.
[26]Reynolds RM and Phillips DI. Long-term consequences of intrauterine growthretardation. Horm Res49,1998; Suppl2:28–31..
[27]Alwasel SH, Ashton N. Prenatal programming of renal sodium handing on the rat.Clin sci2009;117:75-84.
[28]Kagota S, Tamashiro A et al. Downregulation of vascular soluble guanylatecyclase induced by high salt intake in spontaneously hypertensive rats. Br JPharmacol.2001Oct;134(4):737-44.
[29] Ellis A, Goto K, Chaston DJ, Brackenbury TD et al. Enalapril treatment alters thecontribution of epoxyeicosatrienoic acids but not gap junctions toendothelium-derived hyperpolarizing factor activity in mesenteric arteries ofspontaneously hypertensive rats. J Pharmacol Exp Ther.2009Aug;330(2):413-22.
[30] Hae-Ahm Lee, Dong-Youb Lee, Hyo-Jung Lee, Hyung Soo Han and InKyeomKim. Enrichment of (pro)renin receptor promoter with activating histone codes in thekidneys of spontaneously hypertensive rats. J Renin Angiotensin Aldosterone Syst.2012Mar;13(1):11-8.
[31] Rahman M, Kimura S, Nishiyama A, Hitomi H, Zhang G, Abe Y. Angiotensin IIstimulates superoxide production via both angiotensin AT1A and AT1B receptors inmouse aorta and heart. Eur J Pharmacol.2004Feb6;485(1-3):243-9.
[32] Aruna Poduri, A. Phillip Owens, Deborah A. Regional Variation in Aortic AT1bReceptor mRNA Abundance Is Associated with Contractility but Unrelated toAtherosclerosis and Aortic Aneurysms. PLoS One.2012;7(10):e48462.
[33] Yingbi Zhou, Yanfang Chen, Wessel P. AT1b Receptor Predominantly MediatesContractions in Major Mouse Blood Vessels. Circulation Research.2003;93:1089-1094.
[34]Toru Dejima, Kouichi Tamura, Hiromichi Wakui Prepubertal angiotensinblockade exerts long-term therapeutic effect through sustained ATRAP activation insalt-sensitive hypertensive rats. J Hypertens.2011Oct;29(10):1919-29.
[35]Pagtalunan ME, Olson JL, Meyer TW.Contribution of angiotensin II tolate renal injury after acute ischemia.J Am Soc Nephrol,2000,11:1278-86.
[36]Ye M,Wysocki J,Naaz P,et al.Increased ACE2and decreased ACE protein inrenal tubules from diabetic mice:a renoprotective combination? Hypertension,2004,43:1120-5.
[37]Touyz RM.The role of angiotensin II in regulating vascular structural andfunctional changes in hypertension.Curr Hypertens Rep,2003,5:155-64.
[38] Wassmann S,Nickenig G.Pathophysiological regulation of the AT1-receptor andimplications for vascular disease.J Hypertens Suppl,2006,24:S15-21.
[39] Nakashima H,Suzuki H,Ohtsu H,et al.Angiotensin II regulates vascular andendothelial dysfunction:recent topics of Angiotensin II type-1receptor signaling in thevasculature.Curr Vasc Pharmacol,2006,4:67-78.
[40] Pagtalunan ME,Olson JL,Meyer TW.Contribution of angiotensin II to late renalinjury after acute ischemia.J Am Soc Nephrol,2000,11:1278-86.
[41]de Gasparo M,Catt KJ,Inagami T,et al.International union of pharmacology.XXIII.The angiotensin II receptors.Pharmacol Rev,2000,52:415-72.
[42]Conchon S,Monnot C,Teutsch B,et al.Internalization of the rat AT1aand AT1b receptors:pharmacological and functional requirements.FEBS Lett,1994,349:365-70.
[43] Kitami Y, Okura T,Marumoto K,et al.Differential gene expressionand regulation of type-1angiotensin II receptor subtypes in the rat.Biochem Biophys Res Commun,1992,188:446-52.
[44] Paul M,Poyan Mehr A,Kreutz R.Physiology of local renin-angiotensinsystems. Physiol Rev,2006,86:747-803.
[45] Fleming I, Kohlstedt K,Busse R.The tissue renin-angiotensin systemand intracellular signalling.Curr Opin Nephrol Hypertens,2006,15:8-13.
[46] Alam MA, Kauter K, Brown L.Naringin improves diet-induced cardiovasculardysfunction and obesity in high carbohydrate, high fat diet-fed rats. Nutrients.2013Feb27;5(3):637-50.
[47] Samuelsson AM, Matthews PA, Jansen E, Taylor PD, Poston L. Sucrose feedingin mouse pregnancy leads to hypertension, and sex-linked obesity and insulinresistance in female offspring. Front Physiol.2013;4:14.
[48] Lim K, Burke SL, Head GA. Obesity-related hypertension and the role of insulinand leptin in high-fat-fed rabbits. Hypertension.2013Mar;61(3):628-34.
[49]Ding Y, Lv J, Mao C, Zhang H, Wang A, Zhu L, Zhu H, Xu Z. High-salt dietduring pregnancy and angiotensin-related cardiac changes. J Hypertens.2010Jun;28(6):1290-7.
[50]Bogdarina I, Haase A, Langley-Evans S, Clark AJ. Glucocorticoid effects on theprogramming of AT1b angiotensin receptor gene methylation and expression in therat. PLoS One.2010Feb16;5(2):e9237.
[51]Bogdarina IG, King PJ, Clark AJ.Characterization of the angiotensin (AT1b)receptor promoter and its regulation by glucocorticoids. J Mol Endocrinol.2009Aug;43(2):73-80.
[52] CHEN Song-Cang, CHEN Da-Guang. Inhibition of left ventricular hypertrophyand expression of proto-oncogenes c-myc other than c-fos in myocardium by earlycaptopril treatment in SHR rats. Acta Pharmacologica Sinica.1995,3;16(3):217-222.
[1] Tan S X, Li J, Yi H,. Prog Biochem Biophys,2009,36(6):743-749.
[2] McCabe M T, Brandes J C, Vertino P M. Cancer DNA methylation: molecularmechanisms and clinical implications. Clin Cancer Res,2009,15(12):3927-3937
[3] Cotton A M, Avila L, Penaherrera M S, et al. Inactive X chromosome-specificreduction in placental DNA methylation. Hum Mol Genet,2009,18(19):3544-3552
[4] Deng T, Kuang Y, Zhang D, et al. Disruption of imprinting and aberrant embryodevelopment in completely inbred embryonic stem cell-derived mice. Dev GrowthDiffer,2007,49(7):603-610
[5] Gu D F, Reynolds K, Wu X G, et al. Prevalence, awareness, treatment, and controlof hypertension in China. Hypertension,2002,40(6):920-927
[6] Kelly T N, Gu D F, Chen J, et al. Hypertension subtype and risk of cardiovasculardisease in Chinese adults. Circulation,2008,118(15):1558-1566
[7] Bogdarina I, Murphy H C, Burns S P, et al. Investigation of the role of epigeneticmodification of the rat glucokinase gene in fetal programming. Life Sci,2004,74(11):1407-1415
[8] Bogdarina I, Welham S, King P J, et al. Epigenetic modification of therenin-angiotensin system in the fetal programming of hypertension. Circ Res,2007,100(4):520-526
[9] Bogdarina I G, King P J, Clark A J. Characterization of the angiotensin (AT1b)receptor promoter and its regulation by glucocorticoids. J Mol Endocrinol,2009,43(2):73-80
[10]Nuyt A M, Szyf M. Developmental programming through epigenetic changes.Circ Res,2007,100(4):452-455
[11] Yuan H, Huang Z J, Xing X W, et al. Inhibitors of DNA methyltransferase andhistone deacetylase regulate the expression of β1-adrenoceptor gene in myocardialcells. Cell Biol Int,2008,32(3): S7-S8
[12] Draper N, Stewart P M.11-hydroxysteroid dehydrogenase and the pre-receptorregulation of corticosteroid hormone action. J Endocrinol,2005,186(2):251-271
[13] Alikhani-Koopaei R, Fouladkou F, Frey F J, et al. Epigenetic regulation of11β-hydroxysteroid dehydrogenase type2expression. Clin Invest,2004,114(8):1146-1157
[14] Friso S, Pizzolo F, Choi S W, et al. Epigenetic control of11beta-hydroxysteroiddehydrogenase2gene promoter is related to human hypertension. Atherosclerosis,2008,199(2):323-327
[15] Wyrwoll C S, Mark P J, Waddell B J. Developmental programming of renalglucocorticoid sensitivity and the renin-angiotensin system. Hypertension,2007,50(3):579-584
[16] Burns S P, Desai M, Cohen R D, et al. Gluconeogenesis, glucose handling, andstructural changes in livers of the adult offspring of rats partially deprived of proteinduring pregnancy and lactation. J Clin Invest,1997,100(7):1768-1774
[17] Funke-Kaiser H, Reichenberger F, Kopke K, et al. Differential binding oftranscription factor E2F-2to the endothelin-converting enzyme-1b promoter affectsblood pressure regulation. Hum Mol Genet,2003,12(4):423-433
[18] Funke-Kaiser H, Thomas A, Bremer J, et al. Regulation of the major isoform ofhuman endothelin-converting enzyme-1by a strong housekeeping promotermodulated by polymorphic microsatellites. J Hypertens,2003,21(11):2111-2124
[19] Lim U, Cassano P A. Homocysteine and blood pressure in the third nationalhealth and nutrition examination survey,1998-1994. Am J Epidemiol,2002,156(12):1105-1113
[20] Mizrahi E H, Noy S, Sela B A, et al. Further evidence of interrelation betweenhomocysteine and hypertension in stroke patients: a cross-sectional study. Isr MedAssoc J,2003,9(15):791-793
[21] Steed M M, Tyagi N, Moshal K, et al. Homocysteine and oxidative mechanismsof vascular remodeling. FASEB J,2007,21:897.25(Meeting Abstract)
[22]Ovechkin A V, Tyagi N, Sen U, et al.3-Deazaadenosine mitigates arterialremodeling and hypertension in hyperhomocysteinemic mice. Am J Physiol Lung CellMol Physiol,2006,291(5): L905-L911.
[23] Virdis A, Ghiadoni L, Cardinal H, et al. Mechanisms responsible or endothelialdysfunction induced by fasting hyperhomocystinemia n normotensive subjects andpatients with essential hypertension. Am Coll Cardiol,2001,38(4):1106-1115
[24] Ingrosso D, Perna A F. Epigenetics in hyperhomocysteinemic states. specialfocus on uremia. Biochimica et Biophysica Acta,2009,1790(9):892-899
[25] Wilson F A, van den Borne J J, Calder A G, et al. Tissue ethionine cycle activityand homocysteine metabolism in female ats: impact of dietary methionine and folateplus choline. Am Physiol Endocrinol Metab,2009,(4): e702-e713
[26] Kim J M, Hong K, Lee J H. Effect of folate deficiency on lacental DNAmethylation in hyperhomocysteinemic rats. J Nutr Biochem,2009,(3):172-176
[27] Kim J M, Hong K, Lee S,. Folate supplementation to the hyperhomocysteinemicpregnant rats prevent the alteration of homocysteine metabolism and DNAmethylation in the placenta. FASEB J,2007,: A345
[28] Ingrosso D, Cimmino A, Perna A F. Folate treatment and unbalanced methylationand changes of allelic expression induced by hyperhomocysteinaemia in patients withuraemia. Lancet,2003,(9370):1693-1699
[29]Castro R, Rivera I, Struys E A. Increased homocysteine andS-adenosylhomocysteine concentrations and DNA hypomethylation in vasculardisease. Clin Chem,2003,(8):1292-1296
[30] Jiang Y D, Zhang J Z, Huang Y. Prog Biochem Biophys,2007,(5):479-489
[31] Johnson J A, Zineh I, Puckett B J. Beta1-adrenergic receptor polymorphisms andantihypertensive response to metoprolol. Clin Pharmacol Ther,2003,(1):44-52
[32] Evison B J, Bilardi R A, Chiu F C. CpG methylation potentiates pixantrone anddoxorubicin-induced DNA damage and is a marker of drug sensitivity. Nucleic AcidsRes,2009,(19):6355-6370
[33] Zhang Y J, Zhao S L, Tian X Q. Combined inhibition of Dnmt and mTORsignaling inhibits formation and growth of colorectal cancer. Int J Colorectal Dis,2009,(6):629-639
[34] Zhang Z P, Wu M H, Tang H L. Prog Biochem Biophys,2009,(7):904-909
[35] Alyaqoub F S, Tao L H, Kramer P M, et al. Prevention of mouse lung tumors andmodulation of DNA methylation by combined treatment with budesonide andR115777(Zarnestra MT). Carcinogenesis,2007,28(1):124-129
[36]Touyz RM.The role of angiotensin II in regulating vascular structural andfunctional changes in hypertension.Curr Hypertens Rep,2003,5:155-64.
[37] Wassmann S,Nickenig G.Pathophysiological regulation of the AT1-receptor andimplications for vascular disease.J Hypertens Suppl,2006,24:S15-21.
[38] Nakashima H,Suzuki H,Ohtsu H,et al.Angiotensin II regulates vascular andendothelial dysfunction:recent topics of Angiotensin II type-1receptor signaling in thevasculature.Curr Vasc Pharmacol,2006,4:67-78.
[39] Pagtalunan ME,Olson JL,Meyer TW.Contribution of angiotensin II to late renalinjury after acute ischemia.J Am Soc Nephrol,2000,11:1278-86.
[2]Gu D F, Reynolds K, Wu X G, et al. Prevalence, awareness, treatment and controlof hypertension in China. Hypertension,2002,40(6):920-927.
[3]林从容,吴可贵,谢良地,叶琼.血管紧张素Ⅱ一型受体基因A1166C多态性与高血压病的关系.高血压杂志,1999，09.7(3).225-228.
[4]刘晶晶，刑晓为等.β1肾上腺素能受体基因多态性及其甲基化修饰对美托洛尔降压疗效的影响[J].中国动脉硬化杂志，2008，Vol16,3:181-182.
[5]孙红梅,周奇文,吴丽芹.高血压病治疗费用的多因素分析[J].中国医疗前沿2009,15:116.
[6]Ding Y, Lv J, Mao C, Zhang H, Wang A, Zhu L, Zhu H, Xu Z. High-salt dietduring pregnancy and angiotensin-related cardiac changes. J Hypertens.2010Jun;28(6):1290-7. doi:10.1097.
[7] Kosaka S, Pelisch N, Rahman M, Nakano D, Hitomi H, Kobori H, Fukuoka N,Kobara H, Mori H, Masaki T, Cervenka L, Matsumura Y, Houchi H, NishiyamaA.Effects of Angiotensin II AT(1)-Receptor Blockade on High Fat Diet-InducedVascular Oxidative Stress and Endothelial Dysfunction in Dahl Salt-Sensitive Rats. JPharmacol Sci.2013Feb19;121(2):95-102.
[8] Seton-Rogers S. genetics: Methylation in the driver's seat? Nat Rev Cancer.2013Mar;13(3):149.
[9] Macones GA, Odibo A, Cahill A. Discussion:'Hypertension and antihypertensivesin pregnancy,' by Orbach H et al. Am J Obstet Gynecol.2013Feb18. doi:pii:S0002-9378(13)00219-6.
[10] Imran Khan, Vasia Dekou, Mark Hanson, Lucilla Poston and Paul Taylor.Predictive Adaptive Responses to Maternal High-Fat Diet Prevent EndothelialDysfunction but Not Hypertension in Adult Rat Offspring. Circulation2004,110:1097-1102.
[11]Funke-Kaiser H,Reichenberger F,Kopke K,et al.Differential binding oftranscription factor E2F-2to the endothelin-converting enzyme-1b promoter affectsblood pressure regulation.Hum Mol Genet,2003,12(4):423-433.
[12]Funke-Kaiser H,Thomas A,Bremer J,et al.Regulation of the major isoform ofhuman endothelin-converting enzyme-1by a strong housekeeping promotermodulated by polymorphic microsatellites.J Hypertens,2003,21(11):2111-2124.
[13]Bogdarina I G,King P J,Clark A J.Characterization of theangiotensin(AT1b)receptor promoter and its regulation by glucocorticoids.J MolEndocrinol,2009,43(2):73-80.
[14]Nuyt A M,Szyf M.Developmental programming through epigeneticchanges.Circ Res,2007,100(4):452-455.
[15]Yuan H,Huang Z J,Xing X W,et al.Inhibitors of DNA methyltransferase andhistone deacetylase regulate the expression ofβ1-adrenoceptor gene in myocardialcells.Cell Biol Int,2008,32.(3):S7-S8.
[16]Yuan H,Huang Z J,Yang G P,et al.Effects of polymorphism oftheβ1-adrenoreceptor and CYP2D6on the therapeutic effects of metoprolol.J Int MedRes,2008,36(6):1354-1362.
[17]Yuan H,Huang Z J,Liu J J,et al.Influence on metoprolol antihypertensive effectofβ1-adrenoceptor gene polymorphism and methylated modication.Cell BiolInt,2008,32(3):S7.
[18] Ding Y, Lv J, Mao C, Zhang H, Wang A, Zhu L, Zhu H, Xu Z High-salt dietduring pregnancy and angiotensin-related cardiac changes. J Hypertens.2010Jun;28(6):1290-7.
[19] Yutaka Tanakaa, Kouichi Tamuraa, Yuichi Koide, et al. The novel angiotensin IItype1receptor (AT1R)-associated protein ATRAP downregulates AT1R andameliorates cardiomyocyte hypertrophy. FEBS Letters579(2005)1579–1586.
[20]Sluimer JC, Gasc JM, Hamming I, et al. Angiotensin-converting enzyme2(ACE2)expression and activity in human carotid atherosclerotic lesions.JPathol,2008,215:273-9.
[21]Sierra A, Segura J, Banegas JR, et al. Clinical feature of8295patients withresistant hypertension classified on the basis of ambulatory blood pressure monitoring.Hypertension,2011,57:898-902.
[22] Calhoun DA, Jones D, Textor S et al. Resistant hyper-tension: diagnosisEvaluation and treatment: a sci-entific statement from the Am erican HeartAssociation Professional Education Committee of the Council for High BloodPressure Research. Circulation,2008117(25):510-526.
[23] Lowel H, Meisinger C, Heier M et al. Epidemiology of hypertension in Germany.Selected results of population-representative cross-sectional studies. Dtsch MedWochenschr,2006,131:2586-2591.
[24]Barker DJ. The fetal and infant origins of disease. Eur J Clin Invest25:457–463,1995.
[25] Lucas A. Role of nutritional programming in determining adult morbidity. ArchDis Childhood1994;71:288–290,.
[26]Reynolds RM and Phillips DI. Long-term consequences of intrauterine growthretardation. Horm Res49,1998; Suppl2:28–31..
[27]Alwasel SH, Ashton N. Prenatal programming of renal sodium handing on the rat.Clin sci2009;117:75-84.
[28]Kagota S, Tamashiro A et al. Downregulation of vascular soluble guanylatecyclase induced by high salt intake in spontaneously hypertensive rats. Br JPharmacol.2001Oct;134(4):737-44.
[29] Ellis A, Goto K, Chaston DJ, Brackenbury TD et al. Enalapril treatment alters thecontribution of epoxyeicosatrienoic acids but not gap junctions toendothelium-derived hyperpolarizing factor activity in mesenteric arteries ofspontaneously hypertensive rats. J Pharmacol Exp Ther.2009Aug;330(2):413-22.
[30] Hae-Ahm Lee, Dong-Youb Lee, Hyo-Jung Lee, Hyung Soo Han and InKyeomKim. Enrichment of (pro)renin receptor promoter with activating histone codes in thekidneys of spontaneously hypertensive rats. J Renin Angiotensin Aldosterone Syst.2012Mar;13(1):11-8.
[31] Rahman M, Kimura S, Nishiyama A, Hitomi H, Zhang G, Abe Y. Angiotensin IIstimulates superoxide production via both angiotensin AT1A and AT1B receptors inmouse aorta and heart. Eur J Pharmacol.2004Feb6;485(1-3):243-9.
[32] Aruna Poduri, A. Phillip Owens, Deborah A. Regional Variation in Aortic AT1bReceptor mRNA Abundance Is Associated with Contractility but Unrelated toAtherosclerosis and Aortic Aneurysms. PLoS One.2012;7(10):e48462.
[33] Yingbi Zhou, Yanfang Chen, Wessel P. AT1b Receptor Predominantly MediatesContractions in Major Mouse Blood Vessels. Circulation Research.2003;93:1089-1094.
[34]Toru Dejima, Kouichi Tamura, Hiromichi Wakui Prepubertal angiotensinblockade exerts long-term therapeutic effect through sustained ATRAP activation insalt-sensitive hypertensive rats. J Hypertens.2011Oct;29(10):1919-29.
[35]Pagtalunan ME, Olson JL, Meyer TW.Contribution of angiotensin II tolate renal injury after acute ischemia.J Am Soc Nephrol,2000,11:1278-86.
[36]Ye M,Wysocki J,Naaz P,et al.Increased ACE2and decreased ACE protein inrenal tubules from diabetic mice:a renoprotective combination? Hypertension,2004,43:1120-5.
[37]Touyz RM.The role of angiotensin II in regulating vascular structural andfunctional changes in hypertension.Curr Hypertens Rep,2003,5:155-64.
[38] Wassmann S,Nickenig G.Pathophysiological regulation of the AT1-receptor andimplications for vascular disease.J Hypertens Suppl,2006,24:S15-21.
[39] Nakashima H,Suzuki H,Ohtsu H,et al.Angiotensin II regulates vascular andendothelial dysfunction:recent topics of Angiotensin II type-1receptor signaling in thevasculature.Curr Vasc Pharmacol,2006,4:67-78.
[40] Pagtalunan ME,Olson JL,Meyer TW.Contribution of angiotensin II to late renalinjury after acute ischemia.J Am Soc Nephrol,2000,11:1278-86.
[41]de Gasparo M,Catt KJ,Inagami T,et al.International union of pharmacology.XXIII.The angiotensin II receptors.Pharmacol Rev,2000,52:415-72.
[42]Conchon S,Monnot C,Teutsch B,et al.Internalization of the rat AT1aand AT1b receptors:pharmacological and functional requirements.FEBS Lett,1994,349:365-70.
[43] Kitami Y, Okura T,Marumoto K,et al.Differential gene expressionand regulation of type-1angiotensin II receptor subtypes in the rat.Biochem Biophys Res Commun,1992,188:446-52.
[44] Paul M,Poyan Mehr A,Kreutz R.Physiology of local renin-angiotensinsystems. Physiol Rev,2006,86:747-803.
[45] Fleming I, Kohlstedt K,Busse R.The tissue renin-angiotensin systemand intracellular signalling.Curr Opin Nephrol Hypertens,2006,15:8-13.
[46] Alam MA, Kauter K, Brown L.Naringin improves diet-induced cardiovasculardysfunction and obesity in high carbohydrate, high fat diet-fed rats. Nutrients.2013Feb27;5(3):637-50.
[47] Samuelsson AM, Matthews PA, Jansen E, Taylor PD, Poston L. Sucrose feedingin mouse pregnancy leads to hypertension, and sex-linked obesity and insulinresistance in female offspring. Front Physiol.2013;4:14.
[48] Lim K, Burke SL, Head GA. Obesity-related hypertension and the role of insulinand leptin in high-fat-fed rabbits. Hypertension.2013Mar;61(3):628-34.
[49]Ding Y, Lv J, Mao C, Zhang H, Wang A, Zhu L, Zhu H, Xu Z. High-salt dietduring pregnancy and angiotensin-related cardiac changes. J Hypertens.2010Jun;28(6):1290-7.
[50]Bogdarina I, Haase A, Langley-Evans S, Clark AJ. Glucocorticoid effects on theprogramming of AT1b angiotensin receptor gene methylation and expression in therat. PLoS One.2010Feb16;5(2):e9237.
[51]Bogdarina IG, King PJ, Clark AJ.Characterization of the angiotensin (AT1b)receptor promoter and its regulation by glucocorticoids. J Mol Endocrinol.2009Aug;43(2):73-80.
[52] CHEN Song-Cang, CHEN Da-Guang. Inhibition of left ventricular hypertrophyand expression of proto-oncogenes c-myc other than c-fos in myocardium by earlycaptopril treatment in SHR rats. Acta Pharmacologica Sinica.1995,3;16(3):217-222.
[1] Tan S X, Li J, Yi H,. Prog Biochem Biophys,2009,36(6):743-749.
[2] McCabe M T, Brandes J C, Vertino P M. Cancer DNA methylation: molecularmechanisms and clinical implications. Clin Cancer Res,2009,15(12):3927-3937
[3] Cotton A M, Avila L, Penaherrera M S, et al. Inactive X chromosome-specificreduction in placental DNA methylation. Hum Mol Genet,2009,18(19):3544-3552
[4] Deng T, Kuang Y, Zhang D, et al. Disruption of imprinting and aberrant embryodevelopment in completely inbred embryonic stem cell-derived mice. Dev GrowthDiffer,2007,49(7):603-610
[5] Gu D F, Reynolds K, Wu X G, et al. Prevalence, awareness, treatment, and controlof hypertension in China. Hypertension,2002,40(6):920-927
[6] Kelly T N, Gu D F, Chen J, et al. Hypertension subtype and risk of cardiovasculardisease in Chinese adults. Circulation,2008,118(15):1558-1566
[7] Bogdarina I, Murphy H C, Burns S P, et al. Investigation of the role of epigeneticmodification of the rat glucokinase gene in fetal programming. Life Sci,2004,74(11):1407-1415
[8] Bogdarina I, Welham S, King P J, et al. Epigenetic modification of therenin-angiotensin system in the fetal programming of hypertension. Circ Res,2007,100(4):520-526
[9] Bogdarina I G, King P J, Clark A J. Characterization of the angiotensin (AT1b)receptor promoter and its regulation by glucocorticoids. J Mol Endocrinol,2009,43(2):73-80
[10]Nuyt A M, Szyf M. Developmental programming through epigenetic changes.Circ Res,2007,100(4):452-455
[11] Yuan H, Huang Z J, Xing X W, et al. Inhibitors of DNA methyltransferase andhistone deacetylase regulate the expression of β1-adrenoceptor gene in myocardialcells. Cell Biol Int,2008,32(3): S7-S8
[12] Draper N, Stewart P M.11-hydroxysteroid dehydrogenase and the pre-receptorregulation of corticosteroid hormone action. J Endocrinol,2005,186(2):251-271
[13] Alikhani-Koopaei R, Fouladkou F, Frey F J, et al. Epigenetic regulation of11β-hydroxysteroid dehydrogenase type2expression. Clin Invest,2004,114(8):1146-1157
[14] Friso S, Pizzolo F, Choi S W, et al. Epigenetic control of11beta-hydroxysteroiddehydrogenase2gene promoter is related to human hypertension. Atherosclerosis,2008,199(2):323-327
[15] Wyrwoll C S, Mark P J, Waddell B J. Developmental programming of renalglucocorticoid sensitivity and the renin-angiotensin system. Hypertension,2007,50(3):579-584
[16] Burns S P, Desai M, Cohen R D, et al. Gluconeogenesis, glucose handling, andstructural changes in livers of the adult offspring of rats partially deprived of proteinduring pregnancy and lactation. J Clin Invest,1997,100(7):1768-1774
[17] Funke-Kaiser H, Reichenberger F, Kopke K, et al. Differential binding oftranscription factor E2F-2to the endothelin-converting enzyme-1b promoter affectsblood pressure regulation. Hum Mol Genet,2003,12(4):423-433
[18] Funke-Kaiser H, Thomas A, Bremer J, et al. Regulation of the major isoform ofhuman endothelin-converting enzyme-1by a strong housekeeping promotermodulated by polymorphic microsatellites. J Hypertens,2003,21(11):2111-2124
[19] Lim U, Cassano P A. Homocysteine and blood pressure in the third nationalhealth and nutrition examination survey,1998-1994. Am J Epidemiol,2002,156(12):1105-1113
[20] Mizrahi E H, Noy S, Sela B A, et al. Further evidence of interrelation betweenhomocysteine and hypertension in stroke patients: a cross-sectional study. Isr MedAssoc J,2003,9(15):791-793
[21] Steed M M, Tyagi N, Moshal K, et al. Homocysteine and oxidative mechanismsof vascular remodeling. FASEB J,2007,21:897.25(Meeting Abstract)
[22]Ovechkin A V, Tyagi N, Sen U, et al.3-Deazaadenosine mitigates arterialremodeling and hypertension in hyperhomocysteinemic mice. Am J Physiol Lung CellMol Physiol,2006,291(5): L905-L911.
[23] Virdis A, Ghiadoni L, Cardinal H, et al. Mechanisms responsible or endothelialdysfunction induced by fasting hyperhomocystinemia n normotensive subjects andpatients with essential hypertension. Am Coll Cardiol,2001,38(4):1106-1115
[24] Ingrosso D, Perna A F. Epigenetics in hyperhomocysteinemic states. specialfocus on uremia. Biochimica et Biophysica Acta,2009,1790(9):892-899
[25] Wilson F A, van den Borne J J, Calder A G, et al. Tissue ethionine cycle activityand homocysteine metabolism in female ats: impact of dietary methionine and folateplus choline. Am Physiol Endocrinol Metab,2009,(4): e702-e713
[26] Kim J M, Hong K, Lee J H. Effect of folate deficiency on lacental DNAmethylation in hyperhomocysteinemic rats. J Nutr Biochem,2009,(3):172-176
[27] Kim J M, Hong K, Lee S,. Folate supplementation to the hyperhomocysteinemicpregnant rats prevent the alteration of homocysteine metabolism and DNAmethylation in the placenta. FASEB J,2007,: A345
[28] Ingrosso D, Cimmino A, Perna A F. Folate treatment and unbalanced methylationand changes of allelic expression induced by hyperhomocysteinaemia in patients withuraemia. Lancet,2003,(9370):1693-1699
[29]Castro R, Rivera I, Struys E A. Increased homocysteine andS-adenosylhomocysteine concentrations and DNA hypomethylation in vasculardisease. Clin Chem,2003,(8):1292-1296
[30] Jiang Y D, Zhang J Z, Huang Y. Prog Biochem Biophys,2007,(5):479-489
[31] Johnson J A, Zineh I, Puckett B J. Beta1-adrenergic receptor polymorphisms andantihypertensive response to metoprolol. Clin Pharmacol Ther,2003,(1):44-52
[32] Evison B J, Bilardi R A, Chiu F C. CpG methylation potentiates pixantrone anddoxorubicin-induced DNA damage and is a marker of drug sensitivity. Nucleic AcidsRes,2009,(19):6355-6370
[33] Zhang Y J, Zhao S L, Tian X Q. Combined inhibition of Dnmt and mTORsignaling inhibits formation and growth of colorectal cancer. Int J Colorectal Dis,2009,(6):629-639
[34] Zhang Z P, Wu M H, Tang H L. Prog Biochem Biophys,2009,(7):904-909
[35] Alyaqoub F S, Tao L H, Kramer P M, et al. Prevention of mouse lung tumors andmodulation of DNA methylation by combined treatment with budesonide andR115777(Zarnestra MT). Carcinogenesis,2007,28(1):124-129
[36]Touyz RM.The role of angiotensin II in regulating vascular structural andfunctional changes in hypertension.Curr Hypertens Rep,2003,5:155-64.
[37] Wassmann S,Nickenig G.Pathophysiological regulation of the AT1-receptor andimplications for vascular disease.J Hypertens Suppl,2006,24:S15-21.
[38] Nakashima H,Suzuki H,Ohtsu H,et al.Angiotensin II regulates vascular andendothelial dysfunction:recent topics of Angiotensin II type-1receptor signaling in thevasculature.Curr Vasc Pharmacol,2006,4:67-78.
[39] Pagtalunan ME,Olson JL,Meyer TW.Contribution of angiotensin II to late renalinjury after acute ischemia.J Am Soc Nephrol,2000,11:1278-86.