Angiotensin-(1-7) Prevents Cardiomyocyte Pathological Remodeling Through a Nitric Oxide/Guanosine 3′,5′-Cyclic Monophosphate–Dependent Pathway
- 1 January 2010
- journal article
- Published by Ovid Technologies (Wolters Kluwer Health) in Hypertension
- Vol. 55 (1), 153-160
- https://doi.org/10.1161/hypertensionaha.109.143255
Abstract
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 Ca 2+ signaling dysfunction, hypertrophic fetal gene expression, glycogen synthase kinase 3β 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.Keywords
This publication has 32 references indexed in Scilit:
- Phosphodiesterase 5 inhibition blocks pressure overload-induced cardiac hypertrophy independent of the calcineurin pathwayCardiovascular Research, 2008
- Molecular Mechanisms Involved in the Angiotensin-(1-7)/Mas Signaling Pathway in CardiomyocytesHypertension, 2008
- Cardiomyocyte Overexpression of Neuronal Nitric Oxide Synthase Delays Transition Toward Heart Failure in Response to Pressure Overload by Preserving Calcium CyclingCirculation, 2008
- Angiotensin II: A hormone involved in and contributing to pro-hypertrophic cardiac networks and target of anti-hypertrophic cross-talksPharmacology & Therapeutics, 2008
- A Dynamic Pathway for Calcium-Independent Activation of CaMKII by Methionine OxidationCell, 2008
- Glycogen synthase kinase 3 (GSK3) in the heart: a point of integration in hypertrophic signalling and a therapeutic target? A critical analysisBritish Journal of Pharmacology, 2008
- Kinin B1 receptor participates in the control of cardiac function in miceLife Sciences, 2007
- Prevention of angiotensin II-induced cardiac remodeling by angiotensin-(1–7)American Journal of Physiology-Heart and Circulatory Physiology, 2007
- TRPC3 and TRPC6 are essential for angiotensin II-induced cardiac hypertrophyThe EMBO Journal, 2006
- Putting the Brakes on Cardiac HypertrophyHypertension, 2005