辛伐他汀对慢性心力衰竭兔心室重构、心功能的影响及其作用机制
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摘要
研究目的:观察辛伐他汀对慢性心力衰竭兔心室重构、心功能的影响,探讨其作用机制。
研究方法:24只新西兰白兔分为4组,第1组为假手术组,2、3、4组联合应用主动脉瓣破坏术及腹主动脉缩窄术建立慢性心力衰竭模型;第2组为心力衰竭对照组;第3组为早干预组,术后即给予辛伐他汀5mg·kg-1·d-1灌胃,连续6周;第4组为晚干预组,术后4周开始给予辛伐他汀5mg·kg-1·d-1灌胃,连续4周。观察开始及结束时进行超声心动图检查,测量左心室舒张末期内径(LVIDd)、左心室收缩末期内径(LVIDs)、室间隔厚度(IVSd)、左心室后壁厚度(LVPwd)、左心室射血分数(EF)、左心室长轴缩短率(FS)。心导管法记录左心室舒张末压(LVEDP),测量结束后处死动物、取标本。测量心脏重量、左心室重量、心脏/体重、左心室/体重;光镜检查心肌组织切片,TUNEL法检测心肌细胞凋亡指数。RT-PCR检测过氧化物酶体增殖物激活受体(γPPARγ)mRNA水平; Western blotting法测定细胞膜RhoA、细胞浆细胞周期蛋白B1(cyclin B1)、细胞核PPARγ、细胞核核因子-κB(NF-κB)、细胞浆糖原合成激酶3β(GSK3β)、细胞核β-连环蛋白(β-catenin)等蛋白表达水平;用[γ-32P]GTP测定Rho GTPase,免疫沉淀法检测GSK3β活性;电泳迁移率变动分析(EMSA)法测定NF-κB活性。
结果:辛伐他汀早干预组和晚干预组左心室室间隔厚度(IVSd)、左心室收缩期内径(LVIDs)、、左室最大舒张末期压(LVEDP)显著低于心力衰竭对照组,左心室射血分数(EF)、左心室长轴缩短率(FS)显著高于心力衰竭对照组(P<0.05-0.01),心脏重量、左心室重量、心脏/体重、心肌细胞凋亡指数(AI)显著低于心力衰竭对照组(P<0.05-0.01)。另外,辛伐他汀早干预组左心室后壁厚度(LVPWd)、左心室舒张期内径(LVIDd)、左心室/体重显著低于心力衰竭对照组(P<0.05-0.01)。与心力衰竭对照组相比,辛伐他汀早干预组和晚干预组细胞膜RhoA蛋白表达减少(P<0.01)、Rho GTPase活性减弱(P<0.01)、细胞浆cyclinB1蛋白表达减少(P<0.01);细胞核PPARγ基因及蛋白表达增加(P<0.01),细胞核NF-κB活性及蛋白表达降低(P<0.01)、细胞浆GSK3β活性增加(P<0.01)、细胞核β-catenin表达减少(P<0.01)。
结论:在心脏前后负荷增加或心力衰竭发生后,给予辛伐他汀类药,可有效抑制心室肥厚、心肌细胞凋亡,改善心室重构,增强心功能;其机制包括:(1)他汀类药物抑制RhoA蛋白转位于细胞膜,从而抑制Rho GTPase活性,抑制细胞浆cyclinB1蛋白表达,抑制心肌细胞增殖;(2)他汀类药物增加PPARγ基因及蛋白表达,抑制心肌细胞核NFκB亚基p65蛋白表达及活性;(3)增加细胞浆GSK3β活性,抑制心肌细胞核β-catenin表达。
Objection: This study was to evaluate the effects of simvastatin on ventricular remodeling and heart function and investigate the mechanisms of cardioprotective effects of simvastatin.
Methords: 24 rabbits were divided 4 groups, group I: received sham operation as health control. In other groups, aortic regurgitation and coarctation of ascending aorta were operated in rabbits. Group II was received no drugs. In group III, rabbits were given simvastatin 5mg·kg-1·d-1 after the operation. In group IV, rabbits were given simvastatin 5mg·kg-1·d-1 after 4 weeks of operation. At begin and end of treatment period, Echocardiographic evaluations were performed and left ventricular end diastolic pressure was measured with catheter. At the end of experiment, heart weight, left ventricular weight, body weight, heart weight/body weight radio, left ventricular weight/body weight radio were measured.Myocardial apoptosis identified by in situ dUTP nick-end labeling method and apoptotic index (AI) was calculated.Western blotting analysed RhoA expression in cardiomyocyte membrane and cyclin B1 expression in cardiomyocytes cytosol. Rho GTPases activity was determined by [γ-32P] GTP- binding assays. RT-PCR was used to evaluate peroxisome proliferator-activated receptor (PPAR)γmRNA expression. Western blotting analysed PPARγexpression in cardiomyocytes nuclear.Electropharesis mobility shift assay (EMSA) System was used to evaluate NF-κB activity.Western blotting analysed NF-κB expression in cardiomyocytes nuclear. Glycogen Synthase Kinase (GSK)3βactivity was determined by immunoprecipitation.Western blotting analysed GSK3βexpression in cardiomyocytes cytosol andβ-catenin expression in cardiomyocytes unclear.
Results: Compared with CHF rabbits, in rabbits received early and late treatment of simvastatin, the heart weight, left ventricular weight, heart weight/body weight radio were significantly less (p<0.05-0.01, respectively), The IVSd, LVIDs were significantly decreased (p<0.05-0.01, respectively), the EF and FS were significantly higher (p<0.05- 0.01, respectively), The apoptotic index (AP) was significantly less (p<0.01), The LVEDP were significantly lower (p<0.05), cardiomyocyte size decreased. In early treatment group, left ventricular weight/body weight radio, LVIDd and LVPWd were significantly less than CHF rabbits also (p<0.05-0.01, respectively).
In rabbits treated by simvastatin, the expression of RhoA in cardiomyocytes membrane and cyclin B1 in cardiomyocytes cytosol were significantly decreased (p<0.01, respectively). Simvastatin significantly diminished the activity of Rho GTPase (p<0.01, respectively).Simvastatin significantly promoted the PPARγmRNA and protein expression (p<0.01, respectively). The expression and activity of NF-κB were sinificantly inhibited in rabbits treated by simvastatin (p<0.01, respectively).Simvastatin significantly promoted the activity of GSK3βin cardiomyocytes cytosol and significantly reduced the expression ofβ-catenin in cardiomyocytes unclear (p<0.01, respectively).
Conclusion: Given simvastatin in chronic heart failure rabbit models could prevent heart enlarge and inhibit the development of cardiac hypertrophy and prevent the cardiomyocytes apoptosis, improve cardiac function. The mechanisms include: (1) Simvastatin inhibite the expression of RhoA in cardiomyocytes membrane and Rho GTPase activity in cardiomyocytes cytosol.Simvastatin decreae expression of cyclinB1 in cardiomyocytes cytosol. (2) Simvastatin promote PPARγmRNA and protein expression in cardiomyocytes nuclear, inhibite NF-κB expression and activity in cardiomyocytes nuclear. (3)Simvastatin promote GSK3βactivity in cardimyocytes cytosol and reduce the expression ofβ-catenin in cardiomyocytes nuclear.
研究方法:24只新西兰白兔分为4组,第1组为假手术组,2、3、4组联合应用主动脉瓣破坏术及腹主动脉缩窄术建立慢性心力衰竭模型;第2组为心力衰竭对照组;第3组为早干预组,术后即给予辛伐他汀5mg·kg-1·d-1灌胃,连续6周;第4组为晚干预组,术后4周开始给予辛伐他汀5mg·kg-1·d-1灌胃,连续4周。观察开始及结束时进行超声心动图检查,测量左心室舒张末期内径(LVIDd)、左心室收缩末期内径(LVIDs)、室间隔厚度(IVSd)、左心室后壁厚度(LVPwd)、左心室射血分数(EF)、左心室长轴缩短率(FS)。心导管法记录左心室舒张末压(LVEDP),测量结束后处死动物、取标本。测量心脏重量、左心室重量、心脏/体重、左心室/体重;光镜检查心肌组织切片,TUNEL法检测心肌细胞凋亡指数。RT-PCR检测过氧化物酶体增殖物激活受体(γPPARγ)mRNA水平; Western blotting法测定细胞膜RhoA、细胞浆细胞周期蛋白B1(cyclin B1)、细胞核PPARγ、细胞核核因子-κB(NF-κB)、细胞浆糖原合成激酶3β(GSK3β)、细胞核β-连环蛋白(β-catenin)等蛋白表达水平;用[γ-32P]GTP测定Rho GTPase,免疫沉淀法检测GSK3β活性;电泳迁移率变动分析(EMSA)法测定NF-κB活性。
结果:辛伐他汀早干预组和晚干预组左心室室间隔厚度(IVSd)、左心室收缩期内径(LVIDs)、、左室最大舒张末期压(LVEDP)显著低于心力衰竭对照组,左心室射血分数(EF)、左心室长轴缩短率(FS)显著高于心力衰竭对照组(P<0.05-0.01),心脏重量、左心室重量、心脏/体重、心肌细胞凋亡指数(AI)显著低于心力衰竭对照组(P<0.05-0.01)。另外,辛伐他汀早干预组左心室后壁厚度(LVPWd)、左心室舒张期内径(LVIDd)、左心室/体重显著低于心力衰竭对照组(P<0.05-0.01)。与心力衰竭对照组相比,辛伐他汀早干预组和晚干预组细胞膜RhoA蛋白表达减少(P<0.01)、Rho GTPase活性减弱(P<0.01)、细胞浆cyclinB1蛋白表达减少(P<0.01);细胞核PPARγ基因及蛋白表达增加(P<0.01),细胞核NF-κB活性及蛋白表达降低(P<0.01)、细胞浆GSK3β活性增加(P<0.01)、细胞核β-catenin表达减少(P<0.01)。
结论:在心脏前后负荷增加或心力衰竭发生后,给予辛伐他汀类药,可有效抑制心室肥厚、心肌细胞凋亡,改善心室重构,增强心功能;其机制包括:(1)他汀类药物抑制RhoA蛋白转位于细胞膜,从而抑制Rho GTPase活性,抑制细胞浆cyclinB1蛋白表达,抑制心肌细胞增殖;(2)他汀类药物增加PPARγ基因及蛋白表达,抑制心肌细胞核NFκB亚基p65蛋白表达及活性;(3)增加细胞浆GSK3β活性,抑制心肌细胞核β-catenin表达。
Objection: This study was to evaluate the effects of simvastatin on ventricular remodeling and heart function and investigate the mechanisms of cardioprotective effects of simvastatin.
Methords: 24 rabbits were divided 4 groups, group I: received sham operation as health control. In other groups, aortic regurgitation and coarctation of ascending aorta were operated in rabbits. Group II was received no drugs. In group III, rabbits were given simvastatin 5mg·kg-1·d-1 after the operation. In group IV, rabbits were given simvastatin 5mg·kg-1·d-1 after 4 weeks of operation. At begin and end of treatment period, Echocardiographic evaluations were performed and left ventricular end diastolic pressure was measured with catheter. At the end of experiment, heart weight, left ventricular weight, body weight, heart weight/body weight radio, left ventricular weight/body weight radio were measured.Myocardial apoptosis identified by in situ dUTP nick-end labeling method and apoptotic index (AI) was calculated.Western blotting analysed RhoA expression in cardiomyocyte membrane and cyclin B1 expression in cardiomyocytes cytosol. Rho GTPases activity was determined by [γ-32P] GTP- binding assays. RT-PCR was used to evaluate peroxisome proliferator-activated receptor (PPAR)γmRNA expression. Western blotting analysed PPARγexpression in cardiomyocytes nuclear.Electropharesis mobility shift assay (EMSA) System was used to evaluate NF-κB activity.Western blotting analysed NF-κB expression in cardiomyocytes nuclear. Glycogen Synthase Kinase (GSK)3βactivity was determined by immunoprecipitation.Western blotting analysed GSK3βexpression in cardiomyocytes cytosol andβ-catenin expression in cardiomyocytes unclear.
Results: Compared with CHF rabbits, in rabbits received early and late treatment of simvastatin, the heart weight, left ventricular weight, heart weight/body weight radio were significantly less (p<0.05-0.01, respectively), The IVSd, LVIDs were significantly decreased (p<0.05-0.01, respectively), the EF and FS were significantly higher (p<0.05- 0.01, respectively), The apoptotic index (AP) was significantly less (p<0.01), The LVEDP were significantly lower (p<0.05), cardiomyocyte size decreased. In early treatment group, left ventricular weight/body weight radio, LVIDd and LVPWd were significantly less than CHF rabbits also (p<0.05-0.01, respectively).
In rabbits treated by simvastatin, the expression of RhoA in cardiomyocytes membrane and cyclin B1 in cardiomyocytes cytosol were significantly decreased (p<0.01, respectively). Simvastatin significantly diminished the activity of Rho GTPase (p<0.01, respectively).Simvastatin significantly promoted the PPARγmRNA and protein expression (p<0.01, respectively). The expression and activity of NF-κB were sinificantly inhibited in rabbits treated by simvastatin (p<0.01, respectively).Simvastatin significantly promoted the activity of GSK3βin cardiomyocytes cytosol and significantly reduced the expression ofβ-catenin in cardiomyocytes unclear (p<0.01, respectively).
Conclusion: Given simvastatin in chronic heart failure rabbit models could prevent heart enlarge and inhibit the development of cardiac hypertrophy and prevent the cardiomyocytes apoptosis, improve cardiac function. The mechanisms include: (1) Simvastatin inhibite the expression of RhoA in cardiomyocytes membrane and Rho GTPase activity in cardiomyocytes cytosol.Simvastatin decreae expression of cyclinB1 in cardiomyocytes cytosol. (2) Simvastatin promote PPARγmRNA and protein expression in cardiomyocytes nuclear, inhibite NF-κB expression and activity in cardiomyocytes nuclear. (3)Simvastatin promote GSK3βactivity in cardimyocytes cytosol and reduce the expression ofβ-catenin in cardiomyocytes nuclear.
引文
1. Ho KK, Pinsky JL, Kannel WB, et al. The epidemiology of heart failure: the Framingham Study. J Am Coll Cardiol, 1993; 22: 6A–13A.
2. Pfeffer MA, Braunwald E. Ventricular remodeling after myocardial infarction: experimental observation and clinical implications. Circulation, 1990; 81: 1161–1172.
3. Nahrendorf M, Hu K, Hiller KH et al. Impact of hydroxymethylglutaryl coenzyme a reductase inhibition on left ventricular remodeling after myocardial infarction. JACC, 2002; 40: 1695-1700.
4. Hayashidani S, Tsutsui H, Shiomi T et al. Fluvastatin, a 3-Hydroxy-3- Methylglutaryl coenzyme a reductase inhibitor, attenuates left ventricular remodeling and failure after experimental myocardial infarction. Circulation, 2002; 105: 868-873.
5. Bauersachs J, Galuppo P, Fraccarollo D et al. Improvement of left ventricular remodeling and function by hydroxymethylglutaryl coenzyme A reductase inhibition with cerivastatin in rats with heart failure after myocardial infarction.Circulation, 2001; 104: 982-985.
1. Laufs U,Custodis F,B¨ohm M.HMG-CoA reductase inhibitors in chronic heart failure. Drugs, 2006; 66 (2): 145-154.
2. Saka M, Obata K, Ichihara S, et al.Pitavastatin improves cardiac function and survival in association with suppression of the myocardial endothelin system in a rat model of hypertensive heart failure.J Cardiovasc PharmacolTM, 2006; 47: 770– 779.
3. Patel R, Nagueh SF, Tsybouleva N, et al. Simvastatin induces regression of cardiac hypertrophy and fibrosis and improves cardiac function in a transgenic rabbit model of human hypertrophic cardiomyopathy. Ciculation, 2001; 104: 317- 324.
4. Chen MS, Xu FP, Wang GP et al. Statins initiated after hypertrophy inhibit oxidative stress and prevent heart failure in rats with aortic stenosis. J Mol Cell Cardiol, 2004, 37: 889-896.
5. Morikawa-Futamatsu K, Adachi S, Maejima Y,et al.HMG-CoA reductase inhibitor fluvastatin prevents angiotensin II-induced cardiac hypertrophy via Rho kinase and inhibition of cyclin D1.Life Sciences, 2006; 79: 1380–1390.
6. Zile M.Treating diastolic heart failure with Statins.Circulation, 2005; 112: 300- 303.
7. Laufs U, Kilter H, Konkol C et al. Impact of HMG CoA reductase inhibition on small GTPase in the heart. Cardiovasc Res, 2002; 53: 911-920.
8. Planavila A, Laguna JC, Vazquez CM et al. Atorvastatin improves peroxisome proliferators-activated receptor signaling in cardiac hypertrophy by preventing nuclear factor-kB activation. Biochinica Biophysica Acta, 2005; 1687: 76-83.
9. Asakawa M ,Takan o H,Nagai T,et a1.Peroxisome proliferator-aefivated receptorγplays a critical role in inhibition of hypertrophy in vitro and in vivo. Ciroulation, 2002; 105(10): 1240- 1246.
10. Gupta S, Purcell NH, Lin A,et al.Activation of nuclear factor-κB is necessary for myotrophin-induced cardiac hypertrophy.J Cell Bio, 2002; 159 (6): 1019- 1028.
11. Antos CL, McKinsey TA, Frey N, et al. Activated glycogen synthase-3βsuppresses cardiac hypertrophy in vivo. Proc Natl Acad Sci, 2002; 99: 907–912.
12. Cingolani OH.Cardiac hypertrophy and the Wnt/Frizzled pathway. Hypertension, 2007; 49: 427-428.
13. Zorc M, Porenta O V, PleskoviE R Z,et al. Myocytes' apoptosis and proliferation in endomyocardial biopsy as prognostic factors in terminal heart failure. Eur J Physiol, 2001; 442: [Suppl]11: R163-R164.
14. Steenbergen C,Afshari CA,Petranka JG,et al.Alterations in apoptotic signaling in human idiopathic cardiomyopathic hearts in failure. Am J Physiol, 2003: 284 (1): H268-H276.
15. Bergmana MW, Rechner C, Freund C et al. Statins inhibit reoxygenation- induced cardiomyocyte apotosis role for glycogen sythase kinase 3βand transcription factorβ-catenin. J Mol Cell Cardiol, 2004, 37: 681-690.
16. Ogata Y, Takahashi M, Takeuchi K,et al.Fluvastatin induces apoptosis in rat neonatal cardiac myocytes: a possible mechanism of Statin-attenuated cardiac hypertrophy. J Cardiovasc Pharmacol?, 2002; 40: 907-915.
17. Liu HR, Tao L, Gao E,et al. Anti-apoptotic effects of rosiglitazone in hypercholesterolemic rabbits subjected to myocardial ischemia and reperfusion. Cardiovascular Research, 2004; 62: 135– 144.
1. Mackay D, Hall A.Rho GTPases.J Bio Chem, 1998; 273(33): 20685-20688.
2. Ridley AJ.Rho family proteins: coordinating cell responses.Trends Cell Biol, 2001; 11: 471–477.
3. Wettschureck N,Offermanns S.Rho/Rho-kinase mediated signaling in physiology and pathophysiology.J Mol Med, 2002; 80: 629–638.
4. LaMorte VJ, Thorburn J, Absher D, et al. Gq- and Ras-dependent pathways mediate hypertrophy of neonatal rat ventricular myocytes followingα1-adrenergic stimulation.J Biol Chem, 1994; 269:13490–13496.
6. Dorn GW, Brown JH.Gq signaling in cardiac adaptation and maladaptation.Trends in Cardiovasc Med, 1999; 9: 26–34.
7. Adams JW, Sakata Y, Davis MG, et al.Enhanced Gαq signaling: a common pathwaymediates cardiac hypertrophy and apoptotic heart failure.Proc Natl Acad Sci, 1998; 95:10140–10145.
8. Clerk A, Sugden PH. Small guanine nucleotide-binding proteins and myocardial hypertrophy, Circ Res. 2000; 86:1019-23.
9. Maruyama Y, Nishida M, Sugimoto Y, et al. Gα12/13 mediatesα1-adrenergic receptorinduced cardiac hypertrophy.Circ Res, 2002; 91: 961–969.
10. Yanazume T, Hasegawa K, Wada H,et al. Rho/ROCK pathway contributes to theactivation of extracellular signal-regulated kinase/GATA-4 during myocardial cell hypertrophy.J Biol Chem, 2002; 277: 8618–8625.
11. Thorburn J, Xu S, Thorburn A. MAP kinase- and Rho-dependent signals interact to regulate gene expression but not actin morphology in cardiac muscle cells.EMBO J, 1997; 16: 1888–1900.
12. Sah VP, Hoshijima M, Chien KR, Brown JH. Rho is required for Gαq andα1-adrenergic receptor signaling in cardiomyocytes.Dissociation of Ras and Rho pathways.J Biol Chem, 1996; 271: 31185–31190.
13. Sah VP, Minamisawa S, Tam SP, et al.Cardiac-specific overexpression of RhoA results in sinus and atrioventricular nodal dysfunction and contractile failure.J Clin Invest, 1999; 103: 1627–1634.
14. Torsoni AS, Fonseca PM, Crosara-Alberto DP, et al. Early activation of p160ROCK by pressure overload in rat heart. Am J Physiol Cell Physiol, 2003; 284: C1411–C1419. 5. 25. Istvan ES, Deisenhofer J. Structural mechanism for statin inhibition of HMG-CoA reductase. Science, 2001; 292: 1160-1164.
15. Goldstein JL, Brown MS. Regulation of the mevalonate path-way.Nature, 1990; 343: 425-430.
16. Laufs U, Liao JK.Post-transcriptional regulation of endothelial nitric oxide synthase mRNA stability by Rho GTPase.J Biol Chem, 1998; 273: 24266–24271.
17. Laufs U, Kilter H,Konkol C,et al.Impact of HMG CoA reductase inhibition on small GTPases in the heart.Cardiova Res, 2002 (53): 911–920.
18. Masako A, Koji O, Sahoko I, et al. Attenuation of ventricular hypertrophy and fibrosis in rats by pitavastatin: potential role of the RhoA-exreacellular signal-regulated kinase serum response factor signaling pathway.Clinical & Experi Pharmac Physiol, 2006; 33(12): 1164- 1171.
19. Yasuo K, Koji F, Kenichi G, et al. Chronic fluvastatin treatment alters vascular contraction by inhibiting the Rho/Rho-kinase pathway.Clinical & Experi Pharmac Physiol, 2006; 33(8): 673-678.
20. Porter KE. Turne Neil A. O’Regan D J.et al. Simvastatin reduces human atrial myofibroblast proliferation independently of cholesterol lowering via inhibition of RhoA. Cardiovasc Res, 2004; 61: 745– 755.
21. Kozai T,Eto M,Yang Z,et al.Statins prevent pulsatile stretch-induced proliferation of human saphenous vein smooth muscle cells via inhibition of Rho/Rho-kinase pathway. Cardiovasr Res, 2005; 68: 475– 482.
22. Hayashidani S, Tsutsui H, Shiomi T,et al. Fluvastatin, a 3-Hydroxy-3-Methylglutaryl Coenzyme A reductase Inhibitor, attenuates left ventricular remodeling and failure after experimental myocardial infarction.Circulation, 2002; 105: 868-873.
23. Kobayashi N, Horinaka S, Mita S, et al. Critical role of Rho-kinase pathway for cardiac performance and remodeling in failing rat hearts. Cardiovasc Res, 2002; 55: 757–767.
24. Wang YX, da Cunha V, Martin-McNulty B, et al. Inhibition of Rho-kinase by fasudil attenuated angiotensin II-induced cardiac hypertrophy in apolipoprotein E deficient mice.Eur J Pharmacol, 2005; 512: 215–222.
25. Pines J. Cyclins and cyclin-dependent kinase: A biochemica; view. Biochem J, 1995, 308: 697-711.
26. Coleman TR, Dunphy WG.Cdc2 regulatory factors. Curr Opin Cell Biol, 1994, 6: 877-882.
1. Issemann I, Green S. Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature, 1990; 347: 645–650.
2. Brown JD, Plutzky J. Peroxisome proliferator–activated receptors as transcriptional nodal points and therapeutic targets.Circulation, 2007; 115: 518- 533.
3. Duan ZS, Ivashchenko CY, Russell MW,et al. Cardiomyocyte-specific knockout and agonist of peroxisome proliferator–activated receptor-γboth induce cardiac hypertrophy in mice.Circ Res, 2005; 97: 372-379.
4. Dreyer C, Krey G, Keller H, et al. Control of the peroxisomal- oxidation pathway by a novel family of nuclear hormone receptors.Cell, 1992; 68: 879– 888.
5. Tontonoz P., Hu E., Graves RA.et al.mPPAR gamma 2: tissue-specific regulator of an adipocyte enhancer.Genes Dev, 1994; 8:1224–1234.
6. Ijpenberg A, Jeannin E, Wahli W, et al. Polarity and specific sequence requirements of peroxisome proliferator-activated receptor (PPAR)/retinoid X receptor heterodimer binding to DNA: a functional analysis of the malic enzyme gene PPAR response element. J Biol Chem, 1997; 272: 20108–20117.
7. Jamshidi Y, Montgomery HE, Hense HW,et al. Peroxisome proliferator–activated receptorαgene regulates left ventricular growth in response to exercise and hypertension. Circulation, 2002; 105: 950-955.
8. Sack MN, Rader TA, Park SH,et al. Fatty acid oxidation enzyme gene expression is downregulated in the failing heart. Circulation, 1996; 94: 2837– 2842.
9. Dubey RK, Zhang HY, Reddy SR,et al.Pioglitazone attenuates hypertension and inhibits growth of renal arteriolar smooth muscle in rats. Am J Physiol, 1993; 265: R726– 732.
10. Ricote M, Li AC, Willson TM, et al. The peroxisome proliferator-activated receptorγis a negative regulator of macrophage activation. Nature, 1998; 391: 79–82.
11. Shiomi T, Tsutsui H,Hayashidani S ,et al. Pioglitazone,a peroxisome proliferator- activated receptor-γagonist ,attenuates left ventricular remodling and failure afterexperimental myocardial infarction.Circulation,2002; 106: 3126-3132.
12. Asakawa M ,Takano H, Nagai T,et a1.Peroxisome proliferator-aefivated receptorγplays a critical role in inhibition of hypertrophy in vitro and in vivo.Ciroulation, 2002; 105(10): 1240- 1246.
13. Yamamoto K,Ohki R,Lee RT,et a1.Peroxisome proliferator-activated receptors activators inhibit cardiac hypertrophy in cardiac myocytes.Circulation, 2001; 104(14): 1670·1675.
14. Hang F,Wang D,Zhang S,et a1.Peroxisome proliferator activated receptor (PPAR)αagonists inhibit hypertrophy of neonatal rat cardiac myoytes.Endocrinology, 2003; 144(9): 4187-4194.
15. Iglarz M,Touyz RM ,Viel EC,et a1.Peroxisome proliferator-activated receptorαand receptor-γactivators prevent cardiac fibrosis in mineralocoticoid-dependent hypertension. Hypertension,2003; 42(4): 737-743.
16. Calnek DS, Mazzella L, Roser S, Roman J,Hart CM: Peroxisome proliferator- activated receptor gamma ligands increase release of nitric oxide from endothelial cells.Arterioscler Thromb Vasc Biol, 2003; 23: 52–57.
17. Goya K, Sumitani S, Xu X, et al: Peroxisome proliferator-activated receptor alpha agonists increase nitric oxide synthase expression in vascular endothelial cells.Arterioscler Thromb Vasc Biol, 2004; 24: 658–663.
18. Law RE, Goetze S, Xi XP,et al. Expression and function of PPARγin rat and human vascular smooth muscle cells.Circulation, 2000; 101: 1311–1318.
19. Marx N, Schonbeck U, Lazar MA,et al. Peroxisome proliferator- activated receptor- activators inhibit gene expression and migration in human vascular smooth muscle cells.Circ Res, 1998; 83: 1097–1103.
20. Ricote M, Huang J, Fajas L,et al. Expression of the peroxisome proliferator-activated receptorγ(PPARγ) in human atherosclerosis and regulation in macrophages by colony stimulating factors and oxidized low density lipoprotein. Proc Natl Acad Sci, 1998; 95: 7614– 7619.
21. Kotaro T , Toshihiro I , Tomotake T , et al . Peroxisome proliferator- activated receptorγactivators downregulateangiotensin II type 1 receptor in vascular smooth muscle cells. Circulation, 2000; 102: 1834 - 1839.
22. Sugawara A , Takeuchi A , Uruno A , et al .Transcriptional suppression of type 1 angiotensinⅡreceptor gene expression by peroxisome proliferator-activated receptor gamma in vascular smooth muscle cells.Endocrinolog, 2001; 142: 3125 - 3134.
23. Itoh H, Doi K, Tanaka T, et al . Hypertension and insulin resistance: role of peroxisome proliferator-activated receptor gamma. Clin Exp Pharmacol Physiol, 1999; 26: 558 - 560.
24. Moore KJ, Rosen ED, Fitzgerald ML,et al. The role of PPAR-γin macrophage differentiation and cholesterol uptake. Nat Med, 2001; 7: 41–47.
25. Jiang C, Ting A T, Seed B. PPARγagonists inhibit production of monocyte inflammatory cytokines, Nature, 1998, 391: 82 -86.
26. Saki S, Miyauchi T, Irukayama-Tomobe Y, et al. Peroxisome proliferator-activated receptor- gamma activators inhibit endothelin-1-related cardiac hypertrophy in rats. Clin Sci, 2002; 103: 16 s-220 s.
27. Yuan Z, Liu y, Liu Y,et al.Cardioprotective effects of peroxisome proliferator activated receptorγactivators on acute myocarditis: anti-inflammatory actions associated with nuclear factor kB blockade. Heart 2005; 91: 1203–1208.
28. Yamamoto K,Ohki R,Lee R,et al. Peroxisome Proliferator-Activated ReceptorγActivators Inhibit Cardiac Hypertrophy in Cardiac Myocytes.Circulation, 2001; 104: 1670- 1675.
29. Singh H, Sen R, Baltimore D, et al.A nuclear factor that binds to a conserved sequence motive in transcriptional control elements of immunoglobuling genes.Nature, 1986; 319: 154- 158.
30. Baldwin, ASJ.The NF-κB and IκB proteins: new discoveries and insights.Annu. Rev. Immunol, 1996; 14: 649–683.
31. Finco TS, Baldwin AS. Mechanistic aspects of NF-κB regulation: the emerging role ofphosphorylation and proteolysis. Immunity, 1995; 3: 263-272.
32. Zandi DM,Rothwarf M,DelhaseM,et al.The IκB kinase complex (IKK) contains two kinase subunits, IKKαand IKKβ,necessary for IκB phosphorylation and NF-κB activation.Cell, 1997; 91: 243–252.
33. Chen FV, Castranova X, Shi Demers,et al. New insights into the role of nuclear factor-κB, a ubiquitous transcription factor in the initiation of diseases.Clin. Chem, 1999; 45:7–17.
34. Chen ZJ, Parent L, Maniatis T.Site-specific phosphorylation of I-kappa-B-alpha by a novel ubiquitination-dependent protein kinase activity.Cell, 1996; 84; 853—862.
35. Monaco C, Paleolog E. Nuclear factor-κB: a potential therapeutic target in atherosclerosis and thrombosis. Cardiovasc Res, 2004; 61: 671-682.
36. Frantz S, Fraccarllo D,Wagner H, et al. Sustained activation of nuclear factor kappa B and activator protein 1 in chronic heart failure.Cardiovasc Res,2003; 57: 749-756.
37. Gupta S, Purcell NH, Lin A,et al. Activation of nuclear factor-κB is necessary for myotrophin-induced cardiac hypertrophy.J Cell Bio, 2002; 159 (6): 1019- 1028.
38. Purcell NH,Tang G,Yu C,et al.Activation of NF-kB is required for hypertrophic growth of primary rat neonatal ventricular cardiomyocytes.PNAS, 2001; 98 (5):126668–126673.
39. Hirotani S, Otsu K, Nishida K, et al. Involvement of nuclear factor–κB and apoptosis signal- regulating kinase 1 in G-protein–coupled receptoragonist–induced cardiomyocyte hypertrophy.Circulation, 2002; 105: 509–515.
40. Grip O.Janciauskiene S.Lindgren S.Atorvastatin activates PPAR-γand attenuates the inflammatory response in human monocytes.Inflamm res, 2002; 51: 058–062.
41. Planavila A, Laguna JC, Va′zquez-Carrera M. Atorvastatin improves peroxisome proliferator- activated receptor signaling in cardiac hypertrophy by preventing nuclear factor-κB activation. Biochim Biophysic Acta, 2005: 1687; 76– 83.
42. Delerive P,Bossche KD,Besnard S,et al. Peroxisome Proliferator-activated Receptor a Negatively Regulates the Vascular Inflammatory Gene Response by NegativeCross-talk with Transcription Factors NF-kB and AP-1.J Bio Chem.1999;274:(45): 32048–32054.
43. Barger PM , Brandt JM, Leone TC, et al. Deactivation of peroxisome proliferator–activated receptor-a during cardiac hypertrophic growth. J Clin Invest, 2000; 105: 1723–1730.
1. Diehl JA, Cheng M, Roussel MF,et al. Glycogen synthase kinase-3βregulates cyclin D1 proteolysis and subcellular localization.Genes Dev, 1998; 12:3499–3511.
2. Woodgett JR.Regulation and functions of the glycogen synthase kinase-3 subfamily. Sem.Cancer Biol, 1994; 5: 269–275.
3. Hardt S, Sadoshima J.Glycogen synthase kinase-3βa novel regulator of cardiac hypertrophy and development.Circ Res, 2002; 90: 1055- 1063.
4. Morisco C, Zebrowski D, Condorelli G,et al.The Akt-glycogen synthase kinase 3βpathway regulates transcription of atrial natriuretic factor induced byβ- adrenergic receptor stimulation in cardiac myocytes. J Biol Chem, 2000; 275: 14466–14475.
5. Sutherland C, Leighton IA, Cohen P. Inactivation of glycogen synthase kinase-3βby phosphorylation: new kinase connections in insulin and growth-factor signalling. Biochem J, 1993; 296: 15–19.
6. Antos CL, McKinsey TA, Frey N, et al. Activated glycogen synthase-3βsuppresses cardiac hypertrophy in vivo. Proc Natl Acad Sci, 2002; 99: 907–912.
7. Schans V, Borne S, Strzelecka A,et al. Interruption of Wnt signaling attenuates the onset of pressure overload-induced cardiac hypertrophy.Hypertension, 2007; 49: 473 -480.
8. Badorff C, Ruetten H, Mueller S,et al. Fas receptor signaling inhibits glycogensynthase kinase 3βand induces cardiac hypertrophy following pressure overload. J Clin Invest, 2002; 109: 373–381.
9. Parr BA, Shea MJ, Vassileva G, McMahon AP. Mouse Wnt genes exhibit discrete domains of expression in the early embryonic CNS and limb buds.Development, 1993; 119: 247–261.
10. Cingolani OH.Cardiac hypertrophy and the Wnt/Frizzled pathway.Hypertension, 2007; 49: 427-428.
11. Aberle H, Bauer A, Stappert J, et al.β-Catenin is a target for the ubiquitin- proteasome pathway.EMBO J, 1997; 16: 3797–3804.
12. Haq S, Choukroun G, Lim H, et al. Differential activation of signal transduction pathways in human hearts with hypertrophy versus advanced heart failure.Circulation, 2001; 103: 670– 677.
13. Rezvani M, Liew CC. Role of the adenomatous polyposis coli gene product in human cardiac development and disease.J Biol Chem, 2000; 275: 18470–18475.
14. Kikuchi A. Roles of Axin in the Wnt signalling pathway.Cell Signal, 1999; 11:777–788.
1. Lloyd-jones DM, Larson MG, Leip EP et al. Framingham heart study. Lifetime risk for developing congestive heart failure: the Framingham Heart Study [J].Circulation. 2002: 106: 3068-3072.
2. Patel R, Nagueh SF, Tsybouleva N et al. Simvastatin induces regression of cardiac hypertrophy and fibrosis and improves cardiac function in a transgenenic rabbit model of human hypertrophic cardiomyopathy[J].Circulation.2001; 104: 317-324.
3. Ogata Y, Takahashi M, Takeuchi K et al. Fluvastatin induces apoptosis in rat neonatal cardiac myocytes: a possible mechanism of statin-attenuated cardiac hypertrophy [J].J Cardiovasc Pharmacol.2002; 40: 907-915.
4. Nahrendorf M, Hu K, Hiller KH et al. Impact of hydroxymethylglutaryl coenzyme a reductase inhibition on left ventricular remodeling after myocardial infarction [J].JACC.2002; 40: 1695-1700.
5. Nishikawa H, Miura SI, Zhang B et al.Statins induce the regression of left ventricular mass in patients with angina [J].Circ J. 2004; 68: 121-125.
6. Chen MS, Xu FP, Wang YZ et al. Statins initiated after hypertrophy inhibit oxidative stress and prevent heart failure in rats with aortic stenosis[J]. J Mol and cell Cardiol.2004; 37: 889-896.
7. Node K, Fujita M, Kitakaze M et al. Short-term statin therapy improves cardiac function and symptoms in patients with idiopathic dilated cardiomyopath[J]y. Circulation.2003; 108: 839-843.
8. Hayashidani S, Tsutsui H, Shiomi T et al. Fluvastatin, a 3-Hydroxy-3-Methylglutaryl coenzyme a reductase inhibitor, attenuates left ventricular remodeling and failure afterexperimental myocardial infarction [J].Circulation.2002; 105: 868-873.
9. Ray JG, Mamdani MM, Geerts WH. Statin use and survival outcomes in elderly patients with heart failure [J]. Arch Intern Med. 2005; 165: 62-67.
10. Mozaffarian D, Nye R, Levy WC et al. Statin therapy is associated with lower mortality among patients with severe heart failure [J] Am J Cardiol.2004; 93: 1124-1129.
11. Ledoux J, Gee DM, Leblanc N. increased peripheral resistance in heart failure: new evidence suggests an alteration in vascular smooth muscle function [J]. Bri J Pharmacol.2003; 139: 1245-1248.
12. Trochu JN, Mital S, Zhang XP et al. preservation of NO production by statins in the treatment of heart failure[J].Cardiovacul Res.2003; 60: 250-258.
13. Fulton D, Gratton JP, McCabe TJ et al. regulation of endothellum-derived nitric oxide production by the protein kinase Akt[J].Nature.1999, 399: 597-601.
14. Laufs U, Fata VL, Plutzky J et al. Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors [J].Circulation.1998; 97: 1129-1135.
15. Hernandez-Perera O, Perez-Sala D, Soria P et al. Involvement of Rho GTPases in the transcriptional inhibition of preproendothelin-1 gene expression by simvastatin in vascular endothelial cells[J].Cir Res. 2000; 87:616-622.
16. Lee TM, Chou TF, Tsai CH. Effects of pravastatin on cardiomyocyte hypertrophy and ventricular vulnerability in normolipidemic rats after myocardial infarction [J].J Molecul Cell Cardil.2003; 35: 1449-1459.
17. Li JM, Gall AP, Grieve DJ,et al.Activation of NADPH oxidase during progress of cardiac hypertrophy to failure. Hypertension [J].2002; 40: 477-484.
18. Maack C, Kartes T, Kilter H et al. Oxygen free radical release in human failing myocardium is associated with increased activity of Rac1-GTPase and represents a target for statin treatment [J].Circulation.2003; 108: 1567-1574.
19. Obata T, Ebihara A, Yamanaka Y. Effect of fluvastatin, an inhibitor of 3-hydroxy-3- methylglutaryl coenzyme a reductase, on nitric oxide-induced hydroxyl radicalgeneration in the rat heart [J].Biochimica et Biophysica Acta. 2001; 1536: 55-63.
20. Haendeler J, Hoffmann J, Zeiher AM et al. Antioxidant effects of statins via s-nitrosylation and activation of thioredoxin in endothelial cells [J].Circulation.2004; 110: 856-861.
21. Wassmann S, Laufs U, Muller K et al. Cellular antioxidant effects of atorvastatin in vitro and vivo [J] Arterioscler Thromb Vasc Biol. 2002; 22: 300-305.
22. Folkers K, Langsjoen P, Willis R et al. Lovastatin decrease coenzyme Q levels in humans [J]. Proc Natl Acad Sci USA.1990; 87: 8931-8934.
23. Strey CH, Young JM, Molyneux SL et al. Endothelium-ameliorating effects of statin therapy and coenzyme Q10 reductions in chronic heart failure[J].Atherosclerosis.2005; 179: 201-206.
24. Silver MA, Langsjoen PH, Szabo S,et al.Effect of atorvastatin on left ventricular diastolic function and ability of coenzyme Q10 to reverse that dysfunction [J].Am J Cardiol. 2004; 94:13: 1306-1310.
25. Mann DL, Young JB. Basic mechanisms in congestive heart failure: recognizing the role of proinflammatory cytokines [J].Chest.1994; 105: 897-904.
26. Dichtl W, Dulak J, Frick M , et al HMG-CoA reductase inhibition regulate inflammatory transcription factors in human endothelial and vascular smooth muscle cells [J].Arterioscler Thromb Vasc Biol.2003; 23: 58-63.
27. Delerive P, Gervois P, Fruchart JC et al. induction of IkBαexpression as a mechanism contributing to the anti- inflammatory activities of peroxisome proliferators-activated receptor-αactivators[J]. The J Bio Chem. 2000; 275: 36703-36707.
28. Orteqo M, Bustos C, Hernandez-Presa MA et al. Atorvastatin reduces NF-kB activation and chemokine expression in vascular smooth muscle cells and mononuclear cells [J]. Atherosclerosis.1999; 147: 253-261.
29. Grip O, Janciauskiene S, Lindgren S. Atorvastatin activates PPARγand attenuates the inflammatory response in human monocytes [J].Inflamm res. 2002; 51: 58-62.
30. Planavila A, Laguna JC, Vazquez-Carrera M et al.Atorvastatin improves peroxisomeproliferator-activated receptor signaling in cardiac hypertrophy by preventing nuclear factor-κB activation[J]. Biochimica et biophysica Acta. 2005; 1687: 76-83.
31. Laufs U, Kilter H, Konkol C et al. Impact of HMG CoA reductase inhibition on small GTPases in the heart[J].Cardiovas Res. 2002; 53: 911-920.
32. Pap M, Cooper GM. Role of glycogen synthase kinase-3 in the phosphatidylinositol 3-kinase/Akt cell survival pathway [J].J Biolog Chem. 1998; 273: 19929-19932.
33. Bergmann MW, Rechner C, Freund C et al. Statins inhibit reoxygenation-induced cardiomyocyte apoptosis: role for glycogen synthase kinase 3βand transcription factorβ-catenin [J].J Mole and Cell Cardiol.2004 37: 681-690.
34. Ito M, Adachi T, Pimentel DR,et al.Statins inhibit beta-adrenergic receptor-stimulated apoptosis in adult rat ventricular myocytes via a Rac1-dependent mechanism [J].Circulation.2004; 110: 412-418.
35. Bauersachs J, Galuppo P, Fraccarollo D et al. Improvement of left ventricular remodeling and function by hydroxymethylglutaryl coenzyme A reductase inhibition with cerivastatin in rats with heart failure after myocardial infarction [J].Circulation.2001; 104: 982-985.
36. Lou JD, Zhang WW, Zhang GP et al. Simvastatin inhibits noradrenaline-induced hypertrophy of cultured neonatal rat cardiomyocytes [J]. Bri J Pharmaco.2001; 132:159-164.
37. Delbosc S, Cristol JP, Descomps B et al. Simvastatin prevents angiotensinⅡ-induced cardiac alteration and oxidative stress [J].Hypertension. 2002; 40:142-147.
38. Pliquett RU, Cornish KG, Peuler JD et al. Simvastatin normalizes autonomic neural control in experimental heart failure [J].Circulation.2003; 107: 2493-2498.
2. Pfeffer MA, Braunwald E. Ventricular remodeling after myocardial infarction: experimental observation and clinical implications. Circulation, 1990; 81: 1161–1172.
3. Nahrendorf M, Hu K, Hiller KH et al. Impact of hydroxymethylglutaryl coenzyme a reductase inhibition on left ventricular remodeling after myocardial infarction. JACC, 2002; 40: 1695-1700.
4. Hayashidani S, Tsutsui H, Shiomi T et al. Fluvastatin, a 3-Hydroxy-3- Methylglutaryl coenzyme a reductase inhibitor, attenuates left ventricular remodeling and failure after experimental myocardial infarction. Circulation, 2002; 105: 868-873.
5. Bauersachs J, Galuppo P, Fraccarollo D et al. Improvement of left ventricular remodeling and function by hydroxymethylglutaryl coenzyme A reductase inhibition with cerivastatin in rats with heart failure after myocardial infarction.Circulation, 2001; 104: 982-985.
1. Laufs U,Custodis F,B¨ohm M.HMG-CoA reductase inhibitors in chronic heart failure. Drugs, 2006; 66 (2): 145-154.
2. Saka M, Obata K, Ichihara S, et al.Pitavastatin improves cardiac function and survival in association with suppression of the myocardial endothelin system in a rat model of hypertensive heart failure.J Cardiovasc PharmacolTM, 2006; 47: 770– 779.
3. Patel R, Nagueh SF, Tsybouleva N, et al. Simvastatin induces regression of cardiac hypertrophy and fibrosis and improves cardiac function in a transgenic rabbit model of human hypertrophic cardiomyopathy. Ciculation, 2001; 104: 317- 324.
4. Chen MS, Xu FP, Wang GP et al. Statins initiated after hypertrophy inhibit oxidative stress and prevent heart failure in rats with aortic stenosis. J Mol Cell Cardiol, 2004, 37: 889-896.
5. Morikawa-Futamatsu K, Adachi S, Maejima Y,et al.HMG-CoA reductase inhibitor fluvastatin prevents angiotensin II-induced cardiac hypertrophy via Rho kinase and inhibition of cyclin D1.Life Sciences, 2006; 79: 1380–1390.
6. Zile M.Treating diastolic heart failure with Statins.Circulation, 2005; 112: 300- 303.
7. Laufs U, Kilter H, Konkol C et al. Impact of HMG CoA reductase inhibition on small GTPase in the heart. Cardiovasc Res, 2002; 53: 911-920.
8. Planavila A, Laguna JC, Vazquez CM et al. Atorvastatin improves peroxisome proliferators-activated receptor signaling in cardiac hypertrophy by preventing nuclear factor-kB activation. Biochinica Biophysica Acta, 2005; 1687: 76-83.
9. Asakawa M ,Takan o H,Nagai T,et a1.Peroxisome proliferator-aefivated receptorγplays a critical role in inhibition of hypertrophy in vitro and in vivo. Ciroulation, 2002; 105(10): 1240- 1246.
10. Gupta S, Purcell NH, Lin A,et al.Activation of nuclear factor-κB is necessary for myotrophin-induced cardiac hypertrophy.J Cell Bio, 2002; 159 (6): 1019- 1028.
11. Antos CL, McKinsey TA, Frey N, et al. Activated glycogen synthase-3βsuppresses cardiac hypertrophy in vivo. Proc Natl Acad Sci, 2002; 99: 907–912.
12. Cingolani OH.Cardiac hypertrophy and the Wnt/Frizzled pathway. Hypertension, 2007; 49: 427-428.
13. Zorc M, Porenta O V, PleskoviE R Z,et al. Myocytes' apoptosis and proliferation in endomyocardial biopsy as prognostic factors in terminal heart failure. Eur J Physiol, 2001; 442: [Suppl]11: R163-R164.
14. Steenbergen C,Afshari CA,Petranka JG,et al.Alterations in apoptotic signaling in human idiopathic cardiomyopathic hearts in failure. Am J Physiol, 2003: 284 (1): H268-H276.
15. Bergmana MW, Rechner C, Freund C et al. Statins inhibit reoxygenation- induced cardiomyocyte apotosis role for glycogen sythase kinase 3βand transcription factorβ-catenin. J Mol Cell Cardiol, 2004, 37: 681-690.
16. Ogata Y, Takahashi M, Takeuchi K,et al.Fluvastatin induces apoptosis in rat neonatal cardiac myocytes: a possible mechanism of Statin-attenuated cardiac hypertrophy. J Cardiovasc Pharmacol?, 2002; 40: 907-915.
17. Liu HR, Tao L, Gao E,et al. Anti-apoptotic effects of rosiglitazone in hypercholesterolemic rabbits subjected to myocardial ischemia and reperfusion. Cardiovascular Research, 2004; 62: 135– 144.
1. Mackay D, Hall A.Rho GTPases.J Bio Chem, 1998; 273(33): 20685-20688.
2. Ridley AJ.Rho family proteins: coordinating cell responses.Trends Cell Biol, 2001; 11: 471–477.
3. Wettschureck N,Offermanns S.Rho/Rho-kinase mediated signaling in physiology and pathophysiology.J Mol Med, 2002; 80: 629–638.
4. LaMorte VJ, Thorburn J, Absher D, et al. Gq- and Ras-dependent pathways mediate hypertrophy of neonatal rat ventricular myocytes followingα1-adrenergic stimulation.J Biol Chem, 1994; 269:13490–13496.
6. Dorn GW, Brown JH.Gq signaling in cardiac adaptation and maladaptation.Trends in Cardiovasc Med, 1999; 9: 26–34.
7. Adams JW, Sakata Y, Davis MG, et al.Enhanced Gαq signaling: a common pathwaymediates cardiac hypertrophy and apoptotic heart failure.Proc Natl Acad Sci, 1998; 95:10140–10145.
8. Clerk A, Sugden PH. Small guanine nucleotide-binding proteins and myocardial hypertrophy, Circ Res. 2000; 86:1019-23.
9. Maruyama Y, Nishida M, Sugimoto Y, et al. Gα12/13 mediatesα1-adrenergic receptorinduced cardiac hypertrophy.Circ Res, 2002; 91: 961–969.
10. Yanazume T, Hasegawa K, Wada H,et al. Rho/ROCK pathway contributes to theactivation of extracellular signal-regulated kinase/GATA-4 during myocardial cell hypertrophy.J Biol Chem, 2002; 277: 8618–8625.
11. Thorburn J, Xu S, Thorburn A. MAP kinase- and Rho-dependent signals interact to regulate gene expression but not actin morphology in cardiac muscle cells.EMBO J, 1997; 16: 1888–1900.
12. Sah VP, Hoshijima M, Chien KR, Brown JH. Rho is required for Gαq andα1-adrenergic receptor signaling in cardiomyocytes.Dissociation of Ras and Rho pathways.J Biol Chem, 1996; 271: 31185–31190.
13. Sah VP, Minamisawa S, Tam SP, et al.Cardiac-specific overexpression of RhoA results in sinus and atrioventricular nodal dysfunction and contractile failure.J Clin Invest, 1999; 103: 1627–1634.
14. Torsoni AS, Fonseca PM, Crosara-Alberto DP, et al. Early activation of p160ROCK by pressure overload in rat heart. Am J Physiol Cell Physiol, 2003; 284: C1411–C1419. 5. 25. Istvan ES, Deisenhofer J. Structural mechanism for statin inhibition of HMG-CoA reductase. Science, 2001; 292: 1160-1164.
15. Goldstein JL, Brown MS. Regulation of the mevalonate path-way.Nature, 1990; 343: 425-430.
16. Laufs U, Liao JK.Post-transcriptional regulation of endothelial nitric oxide synthase mRNA stability by Rho GTPase.J Biol Chem, 1998; 273: 24266–24271.
17. Laufs U, Kilter H,Konkol C,et al.Impact of HMG CoA reductase inhibition on small GTPases in the heart.Cardiova Res, 2002 (53): 911–920.
18. Masako A, Koji O, Sahoko I, et al. Attenuation of ventricular hypertrophy and fibrosis in rats by pitavastatin: potential role of the RhoA-exreacellular signal-regulated kinase serum response factor signaling pathway.Clinical & Experi Pharmac Physiol, 2006; 33(12): 1164- 1171.
19. Yasuo K, Koji F, Kenichi G, et al. Chronic fluvastatin treatment alters vascular contraction by inhibiting the Rho/Rho-kinase pathway.Clinical & Experi Pharmac Physiol, 2006; 33(8): 673-678.
20. Porter KE. Turne Neil A. O’Regan D J.et al. Simvastatin reduces human atrial myofibroblast proliferation independently of cholesterol lowering via inhibition of RhoA. Cardiovasc Res, 2004; 61: 745– 755.
21. Kozai T,Eto M,Yang Z,et al.Statins prevent pulsatile stretch-induced proliferation of human saphenous vein smooth muscle cells via inhibition of Rho/Rho-kinase pathway. Cardiovasr Res, 2005; 68: 475– 482.
22. Hayashidani S, Tsutsui H, Shiomi T,et al. Fluvastatin, a 3-Hydroxy-3-Methylglutaryl Coenzyme A reductase Inhibitor, attenuates left ventricular remodeling and failure after experimental myocardial infarction.Circulation, 2002; 105: 868-873.
23. Kobayashi N, Horinaka S, Mita S, et al. Critical role of Rho-kinase pathway for cardiac performance and remodeling in failing rat hearts. Cardiovasc Res, 2002; 55: 757–767.
24. Wang YX, da Cunha V, Martin-McNulty B, et al. Inhibition of Rho-kinase by fasudil attenuated angiotensin II-induced cardiac hypertrophy in apolipoprotein E deficient mice.Eur J Pharmacol, 2005; 512: 215–222.
25. Pines J. Cyclins and cyclin-dependent kinase: A biochemica; view. Biochem J, 1995, 308: 697-711.
26. Coleman TR, Dunphy WG.Cdc2 regulatory factors. Curr Opin Cell Biol, 1994, 6: 877-882.
1. Issemann I, Green S. Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature, 1990; 347: 645–650.
2. Brown JD, Plutzky J. Peroxisome proliferator–activated receptors as transcriptional nodal points and therapeutic targets.Circulation, 2007; 115: 518- 533.
3. Duan ZS, Ivashchenko CY, Russell MW,et al. Cardiomyocyte-specific knockout and agonist of peroxisome proliferator–activated receptor-γboth induce cardiac hypertrophy in mice.Circ Res, 2005; 97: 372-379.
4. Dreyer C, Krey G, Keller H, et al. Control of the peroxisomal- oxidation pathway by a novel family of nuclear hormone receptors.Cell, 1992; 68: 879– 888.
5. Tontonoz P., Hu E., Graves RA.et al.mPPAR gamma 2: tissue-specific regulator of an adipocyte enhancer.Genes Dev, 1994; 8:1224–1234.
6. Ijpenberg A, Jeannin E, Wahli W, et al. Polarity and specific sequence requirements of peroxisome proliferator-activated receptor (PPAR)/retinoid X receptor heterodimer binding to DNA: a functional analysis of the malic enzyme gene PPAR response element. J Biol Chem, 1997; 272: 20108–20117.
7. Jamshidi Y, Montgomery HE, Hense HW,et al. Peroxisome proliferator–activated receptorαgene regulates left ventricular growth in response to exercise and hypertension. Circulation, 2002; 105: 950-955.
8. Sack MN, Rader TA, Park SH,et al. Fatty acid oxidation enzyme gene expression is downregulated in the failing heart. Circulation, 1996; 94: 2837– 2842.
9. Dubey RK, Zhang HY, Reddy SR,et al.Pioglitazone attenuates hypertension and inhibits growth of renal arteriolar smooth muscle in rats. Am J Physiol, 1993; 265: R726– 732.
10. Ricote M, Li AC, Willson TM, et al. The peroxisome proliferator-activated receptorγis a negative regulator of macrophage activation. Nature, 1998; 391: 79–82.
11. Shiomi T, Tsutsui H,Hayashidani S ,et al. Pioglitazone,a peroxisome proliferator- activated receptor-γagonist ,attenuates left ventricular remodling and failure afterexperimental myocardial infarction.Circulation,2002; 106: 3126-3132.
12. Asakawa M ,Takano H, Nagai T,et a1.Peroxisome proliferator-aefivated receptorγplays a critical role in inhibition of hypertrophy in vitro and in vivo.Ciroulation, 2002; 105(10): 1240- 1246.
13. Yamamoto K,Ohki R,Lee RT,et a1.Peroxisome proliferator-activated receptors activators inhibit cardiac hypertrophy in cardiac myocytes.Circulation, 2001; 104(14): 1670·1675.
14. Hang F,Wang D,Zhang S,et a1.Peroxisome proliferator activated receptor (PPAR)αagonists inhibit hypertrophy of neonatal rat cardiac myoytes.Endocrinology, 2003; 144(9): 4187-4194.
15. Iglarz M,Touyz RM ,Viel EC,et a1.Peroxisome proliferator-activated receptorαand receptor-γactivators prevent cardiac fibrosis in mineralocoticoid-dependent hypertension. Hypertension,2003; 42(4): 737-743.
16. Calnek DS, Mazzella L, Roser S, Roman J,Hart CM: Peroxisome proliferator- activated receptor gamma ligands increase release of nitric oxide from endothelial cells.Arterioscler Thromb Vasc Biol, 2003; 23: 52–57.
17. Goya K, Sumitani S, Xu X, et al: Peroxisome proliferator-activated receptor alpha agonists increase nitric oxide synthase expression in vascular endothelial cells.Arterioscler Thromb Vasc Biol, 2004; 24: 658–663.
18. Law RE, Goetze S, Xi XP,et al. Expression and function of PPARγin rat and human vascular smooth muscle cells.Circulation, 2000; 101: 1311–1318.
19. Marx N, Schonbeck U, Lazar MA,et al. Peroxisome proliferator- activated receptor- activators inhibit gene expression and migration in human vascular smooth muscle cells.Circ Res, 1998; 83: 1097–1103.
20. Ricote M, Huang J, Fajas L,et al. Expression of the peroxisome proliferator-activated receptorγ(PPARγ) in human atherosclerosis and regulation in macrophages by colony stimulating factors and oxidized low density lipoprotein. Proc Natl Acad Sci, 1998; 95: 7614– 7619.
21. Kotaro T , Toshihiro I , Tomotake T , et al . Peroxisome proliferator- activated receptorγactivators downregulateangiotensin II type 1 receptor in vascular smooth muscle cells. Circulation, 2000; 102: 1834 - 1839.
22. Sugawara A , Takeuchi A , Uruno A , et al .Transcriptional suppression of type 1 angiotensinⅡreceptor gene expression by peroxisome proliferator-activated receptor gamma in vascular smooth muscle cells.Endocrinolog, 2001; 142: 3125 - 3134.
23. Itoh H, Doi K, Tanaka T, et al . Hypertension and insulin resistance: role of peroxisome proliferator-activated receptor gamma. Clin Exp Pharmacol Physiol, 1999; 26: 558 - 560.
24. Moore KJ, Rosen ED, Fitzgerald ML,et al. The role of PPAR-γin macrophage differentiation and cholesterol uptake. Nat Med, 2001; 7: 41–47.
25. Jiang C, Ting A T, Seed B. PPARγagonists inhibit production of monocyte inflammatory cytokines, Nature, 1998, 391: 82 -86.
26. Saki S, Miyauchi T, Irukayama-Tomobe Y, et al. Peroxisome proliferator-activated receptor- gamma activators inhibit endothelin-1-related cardiac hypertrophy in rats. Clin Sci, 2002; 103: 16 s-220 s.
27. Yuan Z, Liu y, Liu Y,et al.Cardioprotective effects of peroxisome proliferator activated receptorγactivators on acute myocarditis: anti-inflammatory actions associated with nuclear factor kB blockade. Heart 2005; 91: 1203–1208.
28. Yamamoto K,Ohki R,Lee R,et al. Peroxisome Proliferator-Activated ReceptorγActivators Inhibit Cardiac Hypertrophy in Cardiac Myocytes.Circulation, 2001; 104: 1670- 1675.
29. Singh H, Sen R, Baltimore D, et al.A nuclear factor that binds to a conserved sequence motive in transcriptional control elements of immunoglobuling genes.Nature, 1986; 319: 154- 158.
30. Baldwin, ASJ.The NF-κB and IκB proteins: new discoveries and insights.Annu. Rev. Immunol, 1996; 14: 649–683.
31. Finco TS, Baldwin AS. Mechanistic aspects of NF-κB regulation: the emerging role ofphosphorylation and proteolysis. Immunity, 1995; 3: 263-272.
32. Zandi DM,Rothwarf M,DelhaseM,et al.The IκB kinase complex (IKK) contains two kinase subunits, IKKαand IKKβ,necessary for IκB phosphorylation and NF-κB activation.Cell, 1997; 91: 243–252.
33. Chen FV, Castranova X, Shi Demers,et al. New insights into the role of nuclear factor-κB, a ubiquitous transcription factor in the initiation of diseases.Clin. Chem, 1999; 45:7–17.
34. Chen ZJ, Parent L, Maniatis T.Site-specific phosphorylation of I-kappa-B-alpha by a novel ubiquitination-dependent protein kinase activity.Cell, 1996; 84; 853—862.
35. Monaco C, Paleolog E. Nuclear factor-κB: a potential therapeutic target in atherosclerosis and thrombosis. Cardiovasc Res, 2004; 61: 671-682.
36. Frantz S, Fraccarllo D,Wagner H, et al. Sustained activation of nuclear factor kappa B and activator protein 1 in chronic heart failure.Cardiovasc Res,2003; 57: 749-756.
37. Gupta S, Purcell NH, Lin A,et al. Activation of nuclear factor-κB is necessary for myotrophin-induced cardiac hypertrophy.J Cell Bio, 2002; 159 (6): 1019- 1028.
38. Purcell NH,Tang G,Yu C,et al.Activation of NF-kB is required for hypertrophic growth of primary rat neonatal ventricular cardiomyocytes.PNAS, 2001; 98 (5):126668–126673.
39. Hirotani S, Otsu K, Nishida K, et al. Involvement of nuclear factor–κB and apoptosis signal- regulating kinase 1 in G-protein–coupled receptoragonist–induced cardiomyocyte hypertrophy.Circulation, 2002; 105: 509–515.
40. Grip O.Janciauskiene S.Lindgren S.Atorvastatin activates PPAR-γand attenuates the inflammatory response in human monocytes.Inflamm res, 2002; 51: 058–062.
41. Planavila A, Laguna JC, Va′zquez-Carrera M. Atorvastatin improves peroxisome proliferator- activated receptor signaling in cardiac hypertrophy by preventing nuclear factor-κB activation. Biochim Biophysic Acta, 2005: 1687; 76– 83.
42. Delerive P,Bossche KD,Besnard S,et al. Peroxisome Proliferator-activated Receptor a Negatively Regulates the Vascular Inflammatory Gene Response by NegativeCross-talk with Transcription Factors NF-kB and AP-1.J Bio Chem.1999;274:(45): 32048–32054.
43. Barger PM , Brandt JM, Leone TC, et al. Deactivation of peroxisome proliferator–activated receptor-a during cardiac hypertrophic growth. J Clin Invest, 2000; 105: 1723–1730.
1. Diehl JA, Cheng M, Roussel MF,et al. Glycogen synthase kinase-3βregulates cyclin D1 proteolysis and subcellular localization.Genes Dev, 1998; 12:3499–3511.
2. Woodgett JR.Regulation and functions of the glycogen synthase kinase-3 subfamily. Sem.Cancer Biol, 1994; 5: 269–275.
3. Hardt S, Sadoshima J.Glycogen synthase kinase-3βa novel regulator of cardiac hypertrophy and development.Circ Res, 2002; 90: 1055- 1063.
4. Morisco C, Zebrowski D, Condorelli G,et al.The Akt-glycogen synthase kinase 3βpathway regulates transcription of atrial natriuretic factor induced byβ- adrenergic receptor stimulation in cardiac myocytes. J Biol Chem, 2000; 275: 14466–14475.
5. Sutherland C, Leighton IA, Cohen P. Inactivation of glycogen synthase kinase-3βby phosphorylation: new kinase connections in insulin and growth-factor signalling. Biochem J, 1993; 296: 15–19.
6. Antos CL, McKinsey TA, Frey N, et al. Activated glycogen synthase-3βsuppresses cardiac hypertrophy in vivo. Proc Natl Acad Sci, 2002; 99: 907–912.
7. Schans V, Borne S, Strzelecka A,et al. Interruption of Wnt signaling attenuates the onset of pressure overload-induced cardiac hypertrophy.Hypertension, 2007; 49: 473 -480.
8. Badorff C, Ruetten H, Mueller S,et al. Fas receptor signaling inhibits glycogensynthase kinase 3βand induces cardiac hypertrophy following pressure overload. J Clin Invest, 2002; 109: 373–381.
9. Parr BA, Shea MJ, Vassileva G, McMahon AP. Mouse Wnt genes exhibit discrete domains of expression in the early embryonic CNS and limb buds.Development, 1993; 119: 247–261.
10. Cingolani OH.Cardiac hypertrophy and the Wnt/Frizzled pathway.Hypertension, 2007; 49: 427-428.
11. Aberle H, Bauer A, Stappert J, et al.β-Catenin is a target for the ubiquitin- proteasome pathway.EMBO J, 1997; 16: 3797–3804.
12. Haq S, Choukroun G, Lim H, et al. Differential activation of signal transduction pathways in human hearts with hypertrophy versus advanced heart failure.Circulation, 2001; 103: 670– 677.
13. Rezvani M, Liew CC. Role of the adenomatous polyposis coli gene product in human cardiac development and disease.J Biol Chem, 2000; 275: 18470–18475.
14. Kikuchi A. Roles of Axin in the Wnt signalling pathway.Cell Signal, 1999; 11:777–788.
1. Lloyd-jones DM, Larson MG, Leip EP et al. Framingham heart study. Lifetime risk for developing congestive heart failure: the Framingham Heart Study [J].Circulation. 2002: 106: 3068-3072.
2. Patel R, Nagueh SF, Tsybouleva N et al. Simvastatin induces regression of cardiac hypertrophy and fibrosis and improves cardiac function in a transgenenic rabbit model of human hypertrophic cardiomyopathy[J].Circulation.2001; 104: 317-324.
3. Ogata Y, Takahashi M, Takeuchi K et al. Fluvastatin induces apoptosis in rat neonatal cardiac myocytes: a possible mechanism of statin-attenuated cardiac hypertrophy [J].J Cardiovasc Pharmacol.2002; 40: 907-915.
4. Nahrendorf M, Hu K, Hiller KH et al. Impact of hydroxymethylglutaryl coenzyme a reductase inhibition on left ventricular remodeling after myocardial infarction [J].JACC.2002; 40: 1695-1700.
5. Nishikawa H, Miura SI, Zhang B et al.Statins induce the regression of left ventricular mass in patients with angina [J].Circ J. 2004; 68: 121-125.
6. Chen MS, Xu FP, Wang YZ et al. Statins initiated after hypertrophy inhibit oxidative stress and prevent heart failure in rats with aortic stenosis[J]. J Mol and cell Cardiol.2004; 37: 889-896.
7. Node K, Fujita M, Kitakaze M et al. Short-term statin therapy improves cardiac function and symptoms in patients with idiopathic dilated cardiomyopath[J]y. Circulation.2003; 108: 839-843.
8. Hayashidani S, Tsutsui H, Shiomi T et al. Fluvastatin, a 3-Hydroxy-3-Methylglutaryl coenzyme a reductase inhibitor, attenuates left ventricular remodeling and failure afterexperimental myocardial infarction [J].Circulation.2002; 105: 868-873.
9. Ray JG, Mamdani MM, Geerts WH. Statin use and survival outcomes in elderly patients with heart failure [J]. Arch Intern Med. 2005; 165: 62-67.
10. Mozaffarian D, Nye R, Levy WC et al. Statin therapy is associated with lower mortality among patients with severe heart failure [J] Am J Cardiol.2004; 93: 1124-1129.
11. Ledoux J, Gee DM, Leblanc N. increased peripheral resistance in heart failure: new evidence suggests an alteration in vascular smooth muscle function [J]. Bri J Pharmacol.2003; 139: 1245-1248.
12. Trochu JN, Mital S, Zhang XP et al. preservation of NO production by statins in the treatment of heart failure[J].Cardiovacul Res.2003; 60: 250-258.
13. Fulton D, Gratton JP, McCabe TJ et al. regulation of endothellum-derived nitric oxide production by the protein kinase Akt[J].Nature.1999, 399: 597-601.
14. Laufs U, Fata VL, Plutzky J et al. Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors [J].Circulation.1998; 97: 1129-1135.
15. Hernandez-Perera O, Perez-Sala D, Soria P et al. Involvement of Rho GTPases in the transcriptional inhibition of preproendothelin-1 gene expression by simvastatin in vascular endothelial cells[J].Cir Res. 2000; 87:616-622.
16. Lee TM, Chou TF, Tsai CH. Effects of pravastatin on cardiomyocyte hypertrophy and ventricular vulnerability in normolipidemic rats after myocardial infarction [J].J Molecul Cell Cardil.2003; 35: 1449-1459.
17. Li JM, Gall AP, Grieve DJ,et al.Activation of NADPH oxidase during progress of cardiac hypertrophy to failure. Hypertension [J].2002; 40: 477-484.
18. Maack C, Kartes T, Kilter H et al. Oxygen free radical release in human failing myocardium is associated with increased activity of Rac1-GTPase and represents a target for statin treatment [J].Circulation.2003; 108: 1567-1574.
19. Obata T, Ebihara A, Yamanaka Y. Effect of fluvastatin, an inhibitor of 3-hydroxy-3- methylglutaryl coenzyme a reductase, on nitric oxide-induced hydroxyl radicalgeneration in the rat heart [J].Biochimica et Biophysica Acta. 2001; 1536: 55-63.
20. Haendeler J, Hoffmann J, Zeiher AM et al. Antioxidant effects of statins via s-nitrosylation and activation of thioredoxin in endothelial cells [J].Circulation.2004; 110: 856-861.
21. Wassmann S, Laufs U, Muller K et al. Cellular antioxidant effects of atorvastatin in vitro and vivo [J] Arterioscler Thromb Vasc Biol. 2002; 22: 300-305.
22. Folkers K, Langsjoen P, Willis R et al. Lovastatin decrease coenzyme Q levels in humans [J]. Proc Natl Acad Sci USA.1990; 87: 8931-8934.
23. Strey CH, Young JM, Molyneux SL et al. Endothelium-ameliorating effects of statin therapy and coenzyme Q10 reductions in chronic heart failure[J].Atherosclerosis.2005; 179: 201-206.
24. Silver MA, Langsjoen PH, Szabo S,et al.Effect of atorvastatin on left ventricular diastolic function and ability of coenzyme Q10 to reverse that dysfunction [J].Am J Cardiol. 2004; 94:13: 1306-1310.
25. Mann DL, Young JB. Basic mechanisms in congestive heart failure: recognizing the role of proinflammatory cytokines [J].Chest.1994; 105: 897-904.
26. Dichtl W, Dulak J, Frick M , et al HMG-CoA reductase inhibition regulate inflammatory transcription factors in human endothelial and vascular smooth muscle cells [J].Arterioscler Thromb Vasc Biol.2003; 23: 58-63.
27. Delerive P, Gervois P, Fruchart JC et al. induction of IkBαexpression as a mechanism contributing to the anti- inflammatory activities of peroxisome proliferators-activated receptor-αactivators[J]. The J Bio Chem. 2000; 275: 36703-36707.
28. Orteqo M, Bustos C, Hernandez-Presa MA et al. Atorvastatin reduces NF-kB activation and chemokine expression in vascular smooth muscle cells and mononuclear cells [J]. Atherosclerosis.1999; 147: 253-261.
29. Grip O, Janciauskiene S, Lindgren S. Atorvastatin activates PPARγand attenuates the inflammatory response in human monocytes [J].Inflamm res. 2002; 51: 58-62.
30. Planavila A, Laguna JC, Vazquez-Carrera M et al.Atorvastatin improves peroxisomeproliferator-activated receptor signaling in cardiac hypertrophy by preventing nuclear factor-κB activation[J]. Biochimica et biophysica Acta. 2005; 1687: 76-83.
31. Laufs U, Kilter H, Konkol C et al. Impact of HMG CoA reductase inhibition on small GTPases in the heart[J].Cardiovas Res. 2002; 53: 911-920.
32. Pap M, Cooper GM. Role of glycogen synthase kinase-3 in the phosphatidylinositol 3-kinase/Akt cell survival pathway [J].J Biolog Chem. 1998; 273: 19929-19932.
33. Bergmann MW, Rechner C, Freund C et al. Statins inhibit reoxygenation-induced cardiomyocyte apoptosis: role for glycogen synthase kinase 3βand transcription factorβ-catenin [J].J Mole and Cell Cardiol.2004 37: 681-690.
34. Ito M, Adachi T, Pimentel DR,et al.Statins inhibit beta-adrenergic receptor-stimulated apoptosis in adult rat ventricular myocytes via a Rac1-dependent mechanism [J].Circulation.2004; 110: 412-418.
35. Bauersachs J, Galuppo P, Fraccarollo D et al. Improvement of left ventricular remodeling and function by hydroxymethylglutaryl coenzyme A reductase inhibition with cerivastatin in rats with heart failure after myocardial infarction [J].Circulation.2001; 104: 982-985.
36. Lou JD, Zhang WW, Zhang GP et al. Simvastatin inhibits noradrenaline-induced hypertrophy of cultured neonatal rat cardiomyocytes [J]. Bri J Pharmaco.2001; 132:159-164.
37. Delbosc S, Cristol JP, Descomps B et al. Simvastatin prevents angiotensinⅡ-induced cardiac alteration and oxidative stress [J].Hypertension. 2002; 40:142-147.
38. Pliquett RU, Cornish KG, Peuler JD et al. Simvastatin normalizes autonomic neural control in experimental heart failure [J].Circulation.2003; 107: 2493-2498.