Angiotensin II: A hormone involved in and contributing to pro-hypertrophic cardiac networks and target of anti-hypertrophic cross-talks

Schlüter, Klaus‐Dieter; Wenzel, Sibylle

doi:10.1016/j.pharmthera.2008.05.010

Cited by 82 publications

(72 citation statements)

References 203 publications

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“…To investigate the potential involvement of miR-21 in pathological cardiac remodeling, we subjected Mir21 -/-mice to 4 different cardiac stresses: (a) acute pressure overload due to TAC (16); (b) chronic calcineurin activation (17); (c) infusion of Ang II, which induces cardiac remodeling through myocyte-autonomous mechanisms and secondary hypertension (18); and (d) myocardial infarction (MI) due to ligation of the proximal left anterior descending (LAD) coronary artery.…”

Section: Resultsmentioning

confidence: 99%

Stress-dependent cardiac remodeling occurs in the absence of microRNA-21 in mice

Patrick¹,

Montgomery²,

Qi³

et al. 2010

J. Clin. Invest.

331

276

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MicroRNAs inhibit mRNA translation or promote mRNA degradation by binding complementary sequences in 3′ untranslated regions of target mRNAs. MicroRNA-21 (miR-21) is upregulated in response to cardiac stress, and its inhibition by a cholesterol-modified antagomir has been reported to prevent cardiac hypertrophy and fibrosis in rodents in response to pressure overload. In contrast, we have shown here that miR-21-null mice are normal and, in response to a variety of cardiac stresses, display cardiac hypertrophy, fibrosis, upregulation of stress-responsive cardiac genes, and loss of cardiac contractility comparable to wildtype littermates. Similarly, inhibition of miR-21 through intravenous delivery of a locked nucleic acid-modified (LNA-modified) antimiR oligonucleotide also failed to block the remodeling response of the heart to stress. We therefore conclude that miR-21 is not essential for pathological cardiac remodeling.

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Section: Resultsmentioning

confidence: 99%

Stress-dependent cardiac remodeling occurs in the absence of microRNA-21 in mice

Patrick¹,

Montgomery²,

Qi³

et al. 2010

J. Clin. Invest.

331

276

View full text Add to dashboard Cite

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“…Ang II acts via Ang II type 1 receptors through 2 major signal transduction pathways; one is associated with G␣12/13 and the other with G␣q. 12 Recently, Takimoto et al 26 have shown a critical role for regulator of G-protein signaling 2 as a brake against the G ␣q /phospholipase C␤ pathway in the early cardiac stress response to pressure overload. Regulator of G-protein signaling 2 activation is mediated by cGMP, suggesting a possible mechanism by which Ang-(1-7) via cGMP antagonizes Ang II actions in cardiac cells.…”

Section: How Does Ang-(1-7) Regulate the Calcineurin/nfat Cascade?mentioning

confidence: 99%

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

et al. 2010

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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 2ϩ signaling dysfunction, hypertrophic fetal gene expression, glycogen synthase kinase 3␤ 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.)

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“…10 Ang-(1-9) is also metabolized by ACE to Ang-(1-7). 11 In the heart, vasculature, and kidneys, Ang- (1)(2)(3)(4)(5)(6)(7) blocks detrimental effects of Ang II via the receptor Mas. 12 For example, Ang-(1-7) blocks Ang II-induced fibrosis, cardiac hypertrophy, and hypertension 13 and in the heart reduces re-entrant arrhythmias.…”

mentioning

confidence: 99%

Angiotensin-(1-9) Attenuates Cardiac Fibrosis in the Stroke-Prone Spontaneously Hypertensive Rat via the Angiotensin Type 2 Receptor

et al. 2012

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Abstract-The renin-angiotensin system regulates cardiovascular physiology via angiotensin II engaging the angiotensin type 1 or type 2 receptors. Classic actions are type 1 receptor mediated, whereas the type 2 receptor may counteract type 1 receptor activity. Angiotensin-converting enzyme 2 metabolizes angiotensin II to angiotensin-(1-7) and angiotensin I to angiotensin-(1-9). Angiotensin-(1-7) antagonizes angiotensin II actions via the receptor Mas. Angiotensin-(1-9) was shown recently to block cardiomyocyte hypertrophy via the angiotensin type 2 receptor. Here, we investigated in vivo effects of angiotensin-(1-9) via the angiotensin type 2 receptor. Angiotensin-(1-9) (100 ng/kg per minute) with or without the angiotensin type 2 receptor antagonist PD123 319 (100 ng/kg per minute) or PD123 319 alone was infused via osmotic minipump for 4 weeks into stroke-prone spontaneously hypertensive rats. We measured blood pressure by radiotelemetry and cardiac structure and function by echocardiography. Angiotensin-(1-9) did not affect blood pressure or left ventricular mass index but reduced cardiac fibrosis by 50% (PϽ0.01) through modulating collagen I expression, reversed by PD123 319 coinfusion. In addition, angiotensin-(1-9) inhibited fibroblast proliferation in vitro in a PD123 319-sensitive manner. Aortic myography revealed that angiotensin-(1-9) significantly increased contraction to phenylephrine compared with controls after N-nitro-L-arginine methyl ester treatment, an effect abolished by PD123 319 coinfusion (area under the curve: angiotensin-(1-9) N-nitro-L-arginine methyl esterϭ98.9Ϯ11.8%; controlϩN-nitro-Larginine methyl esterϭ74.0Ϯ10.4%; PϽ0.01), suggesting that angiotensin-(1-9) improved basal NO bioavailability in an angiotensin type 2 receptor-sensitive manner. In summary, angiotensin-(1-9) reduced cardiac fibrosis and altered aortic contraction via the angiotensin type 2 receptor supporting a direct role for angiotensin-(1-9) in the reninangiotensin system. (Hypertension. 2012;59:300-307.) • Online Data Supplement Key Words: renin-angiotensin system Ⅲ angiotensin-(1-9) Ⅲ cardiac fibrosis Ⅲ angiotensin type 2 receptor Ⅲ stroke-prone spontaneously hypertensive rat A ngiotensin II (Ang II) is the main effector of the renin-angiotensin system (RAS), classically acting via the angiotensin type 1 receptor (AT 1 R) to stimulate effects such as sodium reabsorption, vasoconstriction, proliferation, and inflammation. Ang II, acting via the AT 1 R, contributes to the pathophysiology of cardiovascular disease. The angiotensin type 2 receptor (AT 2 R) is 34% homologous to the AT 1 R, 1 and its actions differ. 2,3 AT 2 R expression is limited to fetal/neonatal tissues 4 ; however, in adult rodents it is upregulated in heart failure and postmyocardial infarction. 5 In human adult myocardium, 41% of angiotensin binding sites are AT 2 Rs. 5 Ang II signaling via the AT 2 R counteracts AT 1 R signaling; for example, blocking AT 2 R activation promotes cardiomyocyte hypertrophy, 2 whereas AT 2 R overexpression in stroke-p...

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Angiotensin II: A hormone involved in and contributing to pro-hypertrophic cardiac networks and target of anti-hypertrophic cross-talks

Cited by 82 publications

References 203 publications

Stress-dependent cardiac remodeling occurs in the absence of microRNA-21 in mice

Stress-dependent cardiac remodeling occurs in the absence of microRNA-21 in mice

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

Angiotensin-(1-9) Attenuates Cardiac Fibrosis in the Stroke-Prone Spontaneously Hypertensive Rat via the Angiotensin Type 2 Receptor

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