Angiotensin-(1-7) Prevents Cardiomyocyte Pathological Remodeling Through a Nitric Oxide/Guanosine 3′,5′-Cyclic Monophosphate-Dependent Pathway

被引:103
作者
Gomes, Eneas R. M.
Lara, Aline A.
Almeida, Pedro W. M.
Guimaraes, Diogo
Resende, Rodrigo R. [2 ]
Campagnole-Santos, Maria J.
Bader, Michael [3 ]
Santos, Robson A. S.
Guatimosim, Silvia [1 ]
机构
[1] Univ Fed Minas Gerais, Inst Biol Sci, Dept Physiol & Biophys, BR-31270901 Belo Horizonte, MG, Brazil
[2] Inst Learning & Res Santa Casa Belo Horizonte, Belo Horizonte, MG, Brazil
[3] Max Delbruck Ctr Mol Med, Berlin, Germany
关键词
cardiomyocytes; NO; cGMP; Ca2+ transient; Ang-(1-7); Ang II; INDUCED CARDIAC-HYPERTROPHY; OXIDE SYNTHASE; PRESSURE-OVERLOAD; SIGNALING PATHWAY; BLOOD-PRESSURE; HEART-FAILURE; GROWTH; MICE; ACTIVATION; EXPRESSION;
D O I
10.1161/HYPERTENSIONAHA.109.143255
中图分类号
R6 [外科学];
学科分类号
1002 ; 100210 ;
摘要
The renin-angiotensin (Ang) system plays a pivotal role in the pathogenesis of cardiovascular disease, with Ang II being the major effector of this system. Multiple lines of evidence have shown that Ang-(1-7) exerts cardioprotective effects in the heart by counterregulating Ang II actions. The questions that remain are how and where Ang-(1-7) exerts its effects. By using a combination of molecular biology, confocal microscopy, and a transgenic rat model with increased levels of circulating Ang-(1-7) (TGR[A1-7]3292), we evaluated the signaling pathways involved in Ang-(1-7) cardioprotection against Ang II-induced pathological remodeling in ventricular cardiomyocytes. Rats were infused with Ang II for 2 weeks. We found that ventricular myocytes from TGR(A1-7)3292 rats are protected from Ang II pathological remodeling characterized by Ca2+ signaling dysfunction, hypertrophic fetal gene expression, glycogen synthase kinase 3 beta inactivation, and nuclear factor of activated T-cells nuclear accumulation. Moreover, cardiomyocytes from TGR(A1-7)3292 rats infused with Ang II presented increased expression levels of neuronal NO synthase. To provide a signaling pathway involved in the beneficial effects of Ang-(1-7), we treated neonatal cardiomyocytes with Ang-(1-7) and Ang II for 36 hours. Treatment of cardiomyocytes with Ang-(1-7) prevented Ang II-induced hypertrophy by modulating calcineurin/nuclear factor of activated T-cell signaling cascade. Importantly, antihypertrophic effects of Ang-(1-7) on Ang II-treated cardiomyocytes were prevented by N-G-nitro-L-arginine methyl ester and 1H-1,2,4oxadiazolo4,2-aquinoxalin-1-one, suggesting that these effects are mediated by NO/cGMP. Taken together, these data reveal a key role for NO/cGMP as a mediator of Ang-(1-7) beneficial effects in cardiac cells. (Hypertension. 2010;55:153-160.)
引用
收藏
页码:153 / U268
页数:18
相关论文
共 39 条
[1]   Nitric oxide regulates the heart by spatial confinement of nitric oxide synthase isoforms [J].
Barouch, LA ;
Harrison, RW ;
Skaf, MW ;
Rosas, GO ;
Cappola, TP ;
Kobeissi, ZA ;
Hobai, IA ;
Lemmon, CA ;
Burnett, AL ;
O'Rourke, B ;
Rodriguez, ER ;
Huang, PL ;
Lima, JAC ;
Berkowitz, DE ;
Hare, JM .
NATURE, 2002, 416 (6878) :337-340
[2]   Nuclear export of NF-ATc enhanced by glycogen synthase kinase-3 [J].
Beals, CR ;
Sheridan, CM ;
Turck, CW ;
Gardner, P ;
Crabtree, GR .
SCIENCE, 1997, 275 (5308) :1930-1933
[3]   Putting the brakes on cardiac hypertrophy - Exploiting the NO-cGMP counter-regulatory system [J].
Booz, GW .
HYPERTENSION, 2005, 45 (03) :341-346
[4]  
BRADFORD MM, 1976, ANAL BIOCHEM, V72, P248, DOI 10.1016/0003-2697(76)90527-3
[5]   The emerging role of neuronal nitric oxide synthase in the regulation of myocardial function [J].
Casadei, Barbara .
EXPERIMENTAL PHYSIOLOGY, 2006, 91 (06) :943-955
[6]   Increased neuronal nitric oxide synthase-derived NO production in the failing human heart [J].
Damy, T ;
Ratajczak, P ;
Shah, AM ;
Camors, E ;
Marty, I ;
Hasenfuss, G ;
Marotte, F ;
Samuel, JL ;
Heymes, C .
LANCET, 2004, 363 (9418) :1365-1367
[7]   Molecular mechanisms involved in the angiotensin-(1-7)/Mas signaling pathway in cardiomyocytes [J].
Dias-Peixoto, Marco F. ;
Santos, Robson A. S. ;
Gomes, Eneas R. M. ;
Alves, Marcia N. M. ;
Almeida, Pedro W. M. ;
Greco, Leonardo ;
Rosa, Mariana ;
Fauler, Beatrix ;
Bader, Michael ;
Alenina, Natalia ;
Guatimosim, Silvia .
HYPERTENSION, 2008, 52 (03) :542-548
[8]   A dynamic pathway for calcium-independent activation of CaMKII by methionine oxidation [J].
Erickson, Jeffrey R. ;
Joiner, Mei-ling A. ;
Guan, Xiaoqun ;
Kutschke, William ;
Yang, Jinying ;
Oddis, Carmine V. ;
Bartlett, Ryan K. ;
Lowe, John S. ;
O'Donnell, Susan E. ;
Aykin-Burns, Nukhet ;
Zimmerman, Matthew C. ;
Zimmerman, Kathy ;
Ham, Amy-Joan L. ;
Weiss, Robert M. ;
Spitz, Douglas R. ;
Shea, Madeline A. ;
Colbran, Roger J. ;
Mohler, Peter J. ;
Anderson, Mark E. .
CELL, 2008, 133 (03) :462-474
[9]   Role of angiotensin II in cardiovascular disease - Therapeutic implications of more than a century of research [J].
Ferrario, CM .
JOURNAL OF THE RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM, 2006, 7 (01) :3-14
[10]   Angiotensin-(1-7): Cardioprotective effect in myocardial ischemia/reperfusion [J].
Ferreira, AJ ;
Santos, RAS ;
Almeida, AP .
HYPERTENSION, 2001, 38 (03) :665-668