Cardiac Angiotensin-(1-7) in Ischemic Cardiomyopathy

Averill, David B.; Ishiyama, Yuichiro; Chappell, Mark C.; Ferrario, Carlos M.

doi:10.1161/01.cir.0000092888.63239.54

Cited by 126 publications

(121 citation statements)

References 32 publications

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“…25 In addition to an intracellular localization within the kidney, 25,26 Ang II has been shown to be in tubular fluid, 27 interstitial fluid compartments, and urine, 1,28 making it available as a substrate for either intracellular or tubular formation of Ang-(1-7). Because ACE2 has been shown to be present in the urine in addition to the tubular location described in these studies (unpublished data from Dr Mark Chappell, 2003), it is likely that it also can be secreted. Thus both renal intracellular and interstitial formation of Ang-(1-7) may occur.…”

Section: Discussionmentioning

confidence: 71%

“…The specificity of the Ang-(1-7) antibody for ICC has been previously described. 16,17 Briefly, it does not cross-react with Ang I or Ang II. The peptide sequence used to make the ACE2 antibody is unique to ACE2 but not ACE or the ACE2 homologue collectrin 18 ; in Western blotting, the antibody recognizes only two bands in the renal cortex at 89 and 125 kDa that correlate with the nonglycosylated and glycosylated forms of ACE2.…”

Section: Immunocytochemistrymentioning

confidence: 99%

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Enhanced Renal Immunocytochemical Expression of ANG-(1-7) and ACE2 During Pregnancy

et al. 2003

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Abstract-Previously we demonstrated that kidney concentration and urinary excretion of angiotensin-(1-7) are increased during normal pregnancy in rats. Since this finding may reflect local kidney production of angiotensin-(1-7), we determined the immunocytochemical distribution of angiotensin-(1-7) and its newly described processing enzyme, ACE2, in kidneys of virgin and 19-day-pregnant Sprague-Dawley rats. Sprague-Dawley rats were killed at the 19th day of pregnancy, and tissues were prepared for immunocytochemical by using a polyclonal antibody to angiotensin-(1-7) or a monoclonal antibody to ACE2. Angiotensin-(1-7) immunostaining was predominantly localized to the renal tubules traversing both the inner cortex and outer medulla. ACE2 immunostaining was localized throughout the cortex and outer medulla and was visualized in the renal tubules of both virgin and pregnant rats. The quantification of angiotensin-(1-7) and ACE2 immunocytochemical staining showed that in pregnant animals, the intensity of the staining increased by 56% and 117%, respectively (PϽ0.05). This first demonstration of the immunocytochemical distribution of angiotensin-(1-7) and ACE2 in kidneys of pregnant rats shows that pregnancy increases angiotensin-(1-7) immunocytochemical expression in association with increased ACE2 intensity of staining. The findings suggest that ACE2 may contribute to the local production and overexpression of angiotensin-(1-7) in the kidney during pregnancy. Key Words: angiotensin Ⅲ renin-angiotensin system Ⅲ pregnancy Ⅲ kidney Ⅲ angiotensin-converting enzyme 2 P reviously we demonstrated for the first time that activation of the renin-angiotensin system (RAS) during pregnancy is associated with augmented kidney concentration and urinary excretion of angiotensin-(1-7) [Ang-(1-7)]. 1 Ang-(1-7), formed from either Ang I or Ang II and shown to exert vasodilatory, antiproliferative and natriuretic effects, 1-9 was the predominate angiotensin peptide found in the kidney and urine of pregnant rats, reaching levels that were 3-and 2.5-fold greater than Ang II in the kidney and urine, respectively. There was an increase in the Ang-(1-7)/Ang II, indicating that there may be increased enzymatic conversion of Ang II into Ang-(1-7). At the same time, there was no change in Ang-(1-7) in the circulation. These findings suggest that there may be an enhanced renal local production and overexpression of Ang-(1-7) in pregnancy without a systemic contribution.The profile of peptides in the kidney with increased content of Ang-(1-7) without a buildup in the levels of Ang II is consistent with an enzymatic pathway of a recently described enzyme of the RAS, ACE2. ACE2 is a carboxypeptidase that converts Ang I into Ang-(1-9), but it also exhibits high catalytic efficiency to generate Ang-(1-7) from Ang II. 10 -12 The ACE2 catalytic activity for Ang II as compared with Ang I is 400-fold higher, making Ang II a central player in the metabolic pathway for the formation of Ang-(1-7). Chappell et al 13 provided the first direct evidence f...

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Section: Discussionmentioning

confidence: 71%

Section: Immunocytochemistrymentioning

confidence: 99%

Enhanced Renal Immunocytochemical Expression of ANG-(1-7) and ACE2 During Pregnancy

et al. 2003

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“…In this regard, there is pharmacological evidence for the presence of a selective Ang-(1-7) receptor in the heart (Ferreira et al, 2001) and coronary arteries (Porsti et al, 1994). In addition, immunoreactivity for Ang-(1-7) was recently detected in cardiac myocites (Averill et al, 2003). Indeed, the recently characterized Ang-(1-7) receptor, Mas , is expressed in the rodent heart (Metzger et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

Evidence for a functional cardiac interaction between losartan and angiotensin‐(1–7) receptors revealed by orthostatic tilting test in rats

Moura¹,

Santos²,

Fontes³

2005

British J Pharmacology

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1 Studies have shown that the angiotensin II (Ang II) AT 1 receptor antagonist, losartan, accentuates the orthostatic hypotensive response in anesthetized rats, and there is evidence indicating that this effect is not exclusively mediated by AT 1 receptors. 2 We investigated whether the pronounced orthostatic cardiovascular response observed in losartantreated rats involves an interference with angiotensin-(1-7) (Ang-(1-7)) receptors. 3 Urethane-anesthetized rats were submitted to orthostatic stress (901 head-up tilt for 2 min). Intravenous injection of losartan (1 mg kg À1 , n ¼ 9) significantly accentuated the decrease in mean arterial pressure (MAP) induced by head-up tilt (À3376% after losartan vs À1578% control tilt). This effect was accompanied by a significant bradycardia (À873% after losartan vs À373% control tilt). Another AT 1 antagonist, candesartan, did not potentiate the decrease of MAP and did not change the cardiac response induced by head-up tilt. Strikingly, administration of the Ang-(1-7) antagonist, A-779 (10 nmol kg À1 , n ¼ 5), totally reversed the bradicardiac effect caused by losartan and this effect was accompanied by a tendency towards attenuation of the hypotensive response caused by losartan. 4 These findings indicate that the marked orthostatic cardiovascular response is specific for losartan, and that it may be due, in part, to an interaction of this antagonist with Ang-(1-7) receptors, probably at the cardiac level.

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“…The heart was our first target in assessing the interactions of ACE2 and Ang-(1-7), because myocytes expressed the components of the system, 43 the ACE2 gene is abundant in the rat heart (Figure 1), and the heptapeptide reversed arrhythmia reperfusion injury. 44 In addition, Loot et al 45 found that chronic infusion of Ang-(1-7) restored cardiac contractility after myocardial infarction (MI).…”

Section: Ace2 and Ang-(1-7)mentioning

confidence: 99%

“…44 In addition, Loot et al 45 found that chronic infusion of Ang-(1-7) restored cardiac contractility after myocardial infarction (MI). Knowledge that the density of Ang-(1-7) immunostaining increased in the penumbra region surrounding the rat ischemic myocardium 43 led us first to evaluate the expression of ACE2 28-days after MI in rats with an associated blockade of AT 1 receptors. 46 A 3-fold increase in ACE2 mRNA within the viable myocardium was found in these experiments, correlating with increases in plasma concentrations of Ang-(1-7).…”

Section: Ace2 and Ang-(1-7)mentioning

confidence: 99%

Angiotensin-Converting Enzyme 2 and Angiotensin-(1-7)

2006

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Abstract-This lecture summarizes the chronology and rationale that led to the discovery of angiotensin-(1-7) as a hormone that, in its own right, opposes the vasoconstrictor and proliferative actions of angiotensin II. The work discussed here additionally analyzes the newest findings on angiotensin-converting enzyme 2, the angiotensin-converting enzyme homologue that efficiently hydrolyzes angiotensin II into angiotensin-(1-7). Both components of this system may significantly influence our future perspective of the role of the renin-angiotensin system, not just in terms of its role in the regulation of cardiovascular and renal function but, moreover, as regulators of a vast array of disease processes in which inflammation and immune mechanisms play a role.

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Cardiac Angiotensin-(1-7) in Ischemic Cardiomyopathy

Cited by 126 publications

References 32 publications

Enhanced Renal Immunocytochemical Expression of ANG-(1-7) and ACE2 During Pregnancy

Enhanced Renal Immunocytochemical Expression of ANG-(1-7) and ACE2 During Pregnancy

Evidence for a functional cardiac interaction between losartan and angiotensin‐(1–7) receptors revealed by orthostatic tilting test in rats

Angiotensin-Converting Enzyme 2 and Angiotensin-(1-7)

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