Angiotensin 1/2 (1-9)

Angiotensin I/II (1-9) is a peptide (ASP-ARG-VAL-TYR-ILE-HIS-PRO-PHE-HIS) containing the amino acids 1-9 that are converted from Angiotensin I/II peptide.

Angiotensin I is formed by the action of renin on angiotensinogen, which has 12 amino acids and is an α-2-globulin produced constitutively and released into the circulation mainly by the liver. Renin cleaves the peptide bond between the leucine (Leu) and valine (Val) residues on angiotensinogen, creating the ten-amino acid peptide angiotensin I. Angiotensin I is converted to angiotensin II (AII) through removal of two C-terminal residues by the enzymeangiotensin-converting enzyme (ACE), primarily through ACE within the lung.

Angiotensin is a peptide hormone that causes vasoconstriction and a subsequent increase in blood pressure. Angiotensin also stimulates the release of aldosterone, which promotes sodium retention in the distal nephron so that drives blood pressure up.

Figure1  Formula of Angiotensin I/II (1-9) 

Ref:

1.  Basso N, Terragno NA (December 2001). "History about the discovery of the renin-angiotensin system". Hypertension 38 (6): 1246–9. 

 2. Richard A. Preston. et. (1998). “Age-Race Subgroup Compared With Renin Profile as Predictors of Blood Pressure Response to Antihypertensive Therapy”. JAMA. 1998;280(13):1168-1172.

3. Williams GH, Dluhy RG (2008). "Chapter 336: Disorders of the Adrenal Cortex". In Loscalzo J, Fauci AS, Braunwald E, Kasper DL, Hauser SL, Longo DL. Harrison's principles of internal medicine. McGraw-Hill Medical.

Angiotensin-converting enzyme 2-Angiotensin 1-7/1-9 system: novel promising targets for heart failure treatment.[Pubmed:28833476]

Fundam Clin Pharmacol. 2018 Feb;32(1):14-25.

Cardiac remodeling (cardiac hypertrophy and fibrosis) is a hallmark of heart failure (HF). It can be induced by the abnormal elevation of several endogenous factors including angiotensin II (Ang II), which is generated from its precursor angiotensin I (Ang I) by the action of angiotensin-converting enzyme. The inhibition of this enzyme or the blockade of the Ang II receptors demonstrated a high clinical value against the progression of HF. Ang I and Ang II may also be converted into angiotensin 1-7 (Ang 1-7) and angiotensin 1-9 (Ang 1-9), respectively, by the action of angiotensin-converting enzyme 2. Both derivatives demonstrated a promising anticardiac remodeling activity especially against the detrimental effects of Ang II. This manuscript thoroughly reviews the available in vitro and in vivo data on Ang 1-7 and Ang 1-9 in the context of the treatment of HF and discusses the associated molecular mechanisms and the trials to clinically utilize Ang 1-7 mimetics for the treatment of that disease.

Primacy of cardiac chymase over angiotensin converting enzyme as an angiotensin-(1-12) metabolizing enzyme.[Pubmed:27465904]

Biochem Biophys Res Commun. 2016 Sep 16;478(2):559-64.

We showed previously that rat angiotensin-(1-12) [Ang-(1-12)] is metabolized by chymase and angiotensin converting enzyme (ACE) to generate Angiotensin II (Ang II). Here, we investigated the affinity of cardiac chymase and ACE enzymes for Ang-(1-12) and Angiotensin I (Ang I) substrates. Native plasma membranes (PMs) isolated from heart and lung tissues of adult spontaneously hypertensive rats (SHR) were incubated with radiolabeled (125)I-Ang-(1-12) or (125)I-Ang I, in the absence or presence of a chymase or ACE inhibitor (chymostatin and lisinopril, respectively). Products were quantitated by HPLC connected to an in-line flow-through gamma detector. The rate of (125)I-Ang II formation from (125)I-Ang-(1-12) by chymase was significantly higher (heart: 7.0 +/- 0.6 fmol/min/mg; lung: 33 +/- 1.2 fmol/min/mg, P < 0.001) when compared to (125)I-Ang I substrate (heart: 0.8 +/- 0.1 fmol/min/mg; lung: 2.1 +/- 0.1 fmol/min/mg). Substrate affinity of (125)I-Ang-(1-12) for rat cardiac chymase was also confirmed using excess unlabeled Ang-(1-12) or Ang I (0-250 muM). The rate of (125)I-Ang II formation was significantly lower using unlabeled Ang-(1-12) compared to unlabeled Ang I substrate. Kinetic data showed that rat chymase has a lower Km (64 +/- 6.3 muM vs 142 +/- 17 muM), higher Vmax (13.2 +/- 1.3 muM/min/mg vs 1.9 +/- 0.2 muM/min/mg) and more than 15-fold higher catalytic efficiency (ratio of Vmax/Km) for Ang-(1-12) compared to Ang I substrate, respectively. We also investigated ACE mediated hydrolysis of (125)I-Ang-(1-12) and (125)I-Ang I in solubilized membrane fractions of the SHR heart and lung. Interestingly, no significant difference in (125)I-Ang II formation by ACE was detected using either substrate, (125)I-Ang-(1-12) or (125)I-Ang I, both in the heart (1.8 +/- 0.2 fmol/min/mg and 1.8 +/- 0.3 fmol/min/mg, respectively) and in the lungs (239 +/- 25 fmol/min/mg and 248 +/- 34 fmol/min/mg, respectively). Compared to chymase, ACE-mediated Ang-(1-12) metabolism in the heart was several fold lower. Overall our findings suggest that Ang-(1-12), not Ang I, is the better substrate for Ang II formation by chymase in adult rats. In addition, this confirms our previous observation that chymase (rather than ACE) is the main hydrolyzing enzyme responsible for Ang II generation from Ang-(1-12) in the adult rat heart.

Angiotensin-(1-5), an active mediator of renin-angiotensin system, stimulates ANP secretion via Mas receptor.[Pubmed:27660028]

Peptides. 2016 Dec;86:33-41.

Angiotensin-(1-5) [Ang-(1-5)], which is a metabolite of Angiotensin-(1-7) [Ang-(1-7)] catalyzed by angiotensin-converting enzyme (ACE), is a pentapeptide of the renin-angiotensin system (RAS). It has been reported that Ang-(1-7) and Ang-(1-9) stimulate the secretion of atrial natriuretic peptide (ANP) via Mas receptor (Mas R) and Ang II type 2 receptor (AT2R), respectively. However, it still remains unknown whether Ang-(1-5) has a similar function to Ang-(1-7). We investigated the effect of Ang-(1-5) on ANP secretion and to define its signaling pathway using isolated perfused beating rat atria. Ang-(1-5) (0.3, 3, 10muM) stimulated high pacing frequency-induced ANP secretion in a dose-dependent manner. Ang-(1-5)-induced ANP secretion (3muM) was attenuated by the pretreatment with an antagonist of Mas R (A-779) but not by an antagonist of AT1R (losartan) or AT2R (PD123,319). An inhibitor for phosphatidylinositol 3-kinase (PI3K; wortmannin), protein kinase B (Akt; API-2), or nitric oxide synthase (NOS; L-NAME) also attenuated the augmentation of ANP secretion induced by Ang-(1-5). Ang-(1-5)-induced ANP secretion was markedly attenuated in isoproterenol-treated hypertrophied atria. The secretagogue effect of Ang-(1-5) on ANP secretion was similar to those induced by Ang-(1-9) and Ang-(1-7). These results suggest that Ang-(1-5) is an active mediator of renin-angiotensin system to stimulate ANP secretion via Mas R and PI3K-Akt-NOS pathway.

Roles of Angiotensin Peptides and Recombinant Human ACE2 in Heart Failure.[Pubmed:28209222]

J Am Coll Cardiol. 2017 Feb 21;69(7):805-819.

BACKGROUND: The renin-angiotensin system (RAS) is activated in heart failure (HF) and inhibition of RAS is a mainstay therapy for HF. Angiotensin-converting enzyme 2 (ACE2) and its product, angiotensin 1-7 (Ang-[1-7]), are important negative regulators of the RAS. OBJECTIVES: A comprehensive examination of angiotensin peptide levels and therapeutic effects of recombinant human ACE2 (rhACE2) on peptide metabolism was evaluated in human plasma and explanted heart tissue from patients with HF. METHODS: Using prospective cohorts with chronic (n = 59) and acute (n = 42) HF, plasma angiotensin analysis was performed using a unique liquid chromatography-mass spectrometry/mass spectroscopy method quantifying circulating and equilibrium levels. Angiotensin II (Ang II) metabolism was examined in human explanted hearts with dilated cardiomyopathy (n = 25). RESULTS: The dynamic range of the RAS was large, with equilibrium angiotensin levels being 8- to 10-fold higher compared with circulating angiotensin levels. In chronic HF patients receiving ACE inhibition, plasma Ang II was suppressed and plasma Ang-(1-7) was elevated, whereas acute HF and patients receiving angiotensin receptor blocker had higher plasma Ang II with lower Ang-(1-7) levels. Suppressed Ang-(1-7)/Ang II ratio was associated with worsening HF symptoms and longer hospitalization. Recombinant human ACE2 effectively metabolized Ang-(1-10) and Ang II into Ang-(1-9) and Ang-(1-7), respectively. Myocardial Ang II levels in explanted human hearts with dilated cardiomyopathy were elevated despite ACE inhibition with elevated chymase activity, and Ang II was effectively converted to Ang-(1-7) by rhACE2. CONCLUSIONS: Plasma angiotensin peptides represent a dynamic network that is altered in HF and in response to rhACE2. An increased plasma Ang-(1-7) level is linked to ACE inhibitor use, whereas acute HF reduced Ang-(1-7) levels and suppressed the Ang-(1-7)/Ang II ratio. Increased chymase activity elevated Ang II levels in failing human hearts. Use of rhACE2 effectively normalized elevated Ang II while increasing Ang-(1-7) and Ang-(1-9) levels.

Relationship between genetic variants of ACE2 gene and circulating levels of ACE2 and its metabolites.[Pubmed:28895159]

J Clin Pharm Ther. 2018 Apr;43(2):189-195.

WHAT IS KNOWN: Angiotensin-converting enzyme 2 (ACE2) plays an important role in the development of essential hypertension (EH). Genetic factors remarkably influence circulating ACE2 level. OBJECTIVE: Because heritability had remarkable effects on circulating ACE2, we designed this study to shed light on whether circulating levels of ACE2, angiotensin-(1-7) and angiotensin-(1-9) were linked to single nucleotide polymorphisms (SNPs) and haplotypes in ACE2 gene. METHODS: A total of 213 patients with newly diagnosed mild to moderate EH were enrolled in the present study. Four ACE2 tag SNPs (rs2074192, rs4646171, rs4646155 and rs2106809) were genotyped, and major haplotypes consisting of these 4 SNPs were reconstructed for all subjects. Circulating levels of ACE2, angiotensin-(1-7) and angiotensin-(1-9) were measured using enzyme-linked immunosorbent assay. RESULTS: In female subjects, linear regression analysis suggested that rare alleles of ACE2 rs2074192 and rs2106809 were associated with reduced circulating angiotensin-(1-7) levels (P=.007 and P=.006, respectively). ACE2 haplotype CAGC was associated with elevated circulating angiotensin-(1-7) levels (P=.03) whereas TAGT was associated with reduced circulating angiotensin-(1-7) levels in females (P<.001). Univariate linear regression analysis revealed that circulating ACE2 levels were positively associated with systolic blood pressure (P=.02), mean arterial pressure (P=.02) and serum creatinine (P<.001) in females whereas circulating ACE2 levels were positively associated with age (P<.001) and serum creatinine (P<.001) in males. WHAT IS NEW AND CONCLUSION: ACE2 SNPs and haplotypes are associated with circulating angiotensin-(1-7) levels. ACE2 genetic variants may be the determinants of circulating angiotensin-(1-7) levels in hypertensive females.