Angiotensin-(1–9) regulates cardiac hypertrophy in vivo and in vitro

Ocaranza, María Paz; Lavandero, Sergio; Jalil, Jorge; Moya, Jaqueline; Pinto, Melissa; Novoa, Ulises; Apablaza, Felipe; González, López; Hernandez, Carol; Varas, Manuel; López, René; Godoy, Iván; Verdejo, Hugo; Chiong, Mario

doi:10.1097/hjh.0b013e328335d291

Cited by 89 publications

(108 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…16 Recently Ang-(1-9) was demonstrated to inhibit cardiac hypertrophy after myocardial infarction in rats. 17 This was not dependent on Ang-(1-9) to Ang-(1-7) conversion, because coadministration of the Mas antagonist A779 did not influence the effects of Ang-(1-9). However, Ang-(1-9) administration did lead to decreased Ang II levels.…”

mentioning

confidence: 91%

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

et al. 2012

View full text Add to dashboard Cite

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...

show abstract

mentioning

confidence: 91%

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

et al. 2012

View full text Add to dashboard Cite

show abstract

“…Ace and Ace2 are tethered to endothelial cell membrane or secreted into the interstitial space, where these enzymes process Ang I and II peptides. Biochemically, Ace converts the decapeptide Ang I (1-12) to octapeptide Ang II (1-10), whereas Ace2 degrades Ang II to form Ang-(1-7) (16) and cleaves Ang I into Ang-(1-9) (17). Functionally, Ang II is a potent stimulant of cardiac hypertrophy and fibrosis (8); conversely, Ang-(1-7) and Ang-(1-9) inhibit Ang II's cardiac effects to maintain heart function (8,18).…”

mentioning

confidence: 99%

Pathological Ace2-to-Ace enzyme switch in the stressed heart is transcriptionally controlled by the endothelial Brg1–FoxM1 complex

Yang

Feng

Zhou

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Genes encoding angiotensin-converting enzymes (Ace and Ace2) are essential for heart function regulation. Cardiac stress enhances Ace, but suppresses Ace2, expression in the heart, leading to a net production of angiotensin II that promotes cardiac hypertrophy and fibrosis. The regulatory mechanism that underlies the Ace2-to-Ace pathological switch, however, is unknown. Here we report that the Brahma-related gene-1 (Brg1) chromatin remodeler and forkhead box M1 (FoxM1) transcription factor cooperate within cardiac (coronary) endothelial cells of pathologically stressed hearts to trigger the Ace2-to-Ace enzyme switch, angiotensin I-to-II conversion, and cardiac hypertrophy. In mice, cardiac stress activates the expression of Brg1 and FoxM1 in endothelial cells. Once activated, Brg1 and FoxM1 form a protein complex on Ace and Ace2 promoters to concurrently activate Ace and repress Ace2, tipping the balance to Ace2 expression with enhanced angiotensin II production, leading to cardiac hypertrophy and fibrosis. Disruption of endothelial Brg1 or FoxM1 or chemical inhibition of FoxM1 abolishes the stress-induced Ace2-to-Ace switch and protects the heart from pathological hypertrophy. In human hypertrophic hearts, BRG1 and FOXM1 expression is also activated in endothelial cells; their expression levels correlate strongly with the ACE/ACE2 ratio, suggesting a conserved mechanism. Our studies demonstrate a molecular interaction of Brg1 and FoxM1 and an endothelial mechanism of modulating Ace/Ace2 ratio for heart failure therapy.

show abstract

“…Por otra parte, los resultados del presente estudio muestran que la administración crónica de Ang-(1-9), en un modelo experimental de ratas previamente hipertensas, logró revertir la hipertrofia cardíaca, destacando que este efecto tampoco fue mediado por Ang-(1-7). Éstos resultados complementan observaciones previas de nuestro grupo, que evidenciaron que Ang-(1-9) previno la HTA 13 y disminuyó la hipertrofia cardiaca tanto in vivo and in vitro 10 . Además, Flores et al (2011) apoyó el concepto que Ang-(1-9) es un péptido con propiedades anti-hipertróficas, cuyo mecanismo de acción era vía el receptor tipo 2 de Angiotensina II (AT2R) 24 .…”

Section: Discussionunclassified

“…Por lo tanto, estos antecedentes proponen un rol contrarregulador del eje Ang-(1-7)/ECA2/MAShacia el eje ECA/Ang I/receptor AT1 en el sistema Renina-Angiotensina-Aldosterona (SRA) [7][8] . Respecto a Ang-1-9, en estudios previos realizados por nuestro grupo hemos propuesto que el péptido Ang-(1-9) podría actuar como un contrarregulador de Ang II más efectivo que Ang-(1-7) [9][10] . Además, hemos determinado que Ang-(1-9) previene el desarrollo de hipertrofia cardía-ca in vitro e in vivo, independiente del receptor de Ang-(1-7), MAS 10 .…”

Section: Introductionunclassified

“…Respecto a Ang-1-9, en estudios previos realizados por nuestro grupo hemos propuesto que el péptido Ang-(1-9) podría actuar como un contrarregulador de Ang II más efectivo que Ang-(1-7) [9][10] . Además, hemos determinado que Ang-(1-9) previene el desarrollo de hipertrofia cardía-ca in vitro e in vivo, independiente del receptor de Ang-(1-7), MAS 10 . En otro estudio hemos observado una disminución significativa de los niveles de Ang-(1-9) y de ECA2 en la pared aórtica en el modelo de animales con HTA y remodelamiento cardiovascular hipertensivo [11][12] .…”

Section: Introductionunclassified

See 1 more Smart Citation

El efecto anti-hipertensivo de Angiotensina-(1-9) es mediado por aumento temprano de la diuresis y natriuresis

et al. 2015

Self Cite

View full text Add to dashboard Cite

Angiotensin-(1–9) regulates cardiac hypertrophy in vivo and in vitro

Abstract: Angiotensin-(1-9) is an effective and a novel anti-cardiac hypertrophy agent not acting via the Mas receptor.

Cited by 89 publications

References 40 publications

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

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

Pathological Ace2-to-Ace enzyme switch in the stressed heart is transcriptionally controlled by the endothelial Brg1–FoxM1 complex

El efecto anti-hipertensivo de Angiotensina-(1-9) es mediado por aumento temprano de la diuresis y natriuresis

Contact Info

Product

Resources

About