Angiotensin II AT<sub>1</sub> receptors regulate ACE2 and angiotensin-(1–7) expression in the aorta of spontaneously hypertensive rats

Igase, Michiya; Strawn, William B.; Gallagher, Patricia E.; Geary, Randolph L.; Ferrario, Carlos M.

doi:10.1152/ajpheart.00068.2005

Cited by 199 publications

(185 citation statements)

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“…In this study, we showed increased ACE2 gene expression in the aorta but not the carotid arteries of SHRs given olmesartan for 2 weeks. 50 Additional evidence for a transcriptional regulation of the ACE2 enzyme is found in the data obtained by Gallagher et al 51 in neonatal rat cerebellar or medullary astrocytes. In these studies, we showed that Ang II-mediated reduction in ACE2 mRNA was blocked by losartan or valsartan, whereas PD123319 was ineffective.…”

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

confidence: 83%

“…Treatment with Ang-(1-7) resulted in both a dose-and time-dependent reduction in serum-stimulated DNA synthesis in all 3 of the cell lines, with an IC 50 in the subnanomolar range. The Ang-(1-7) receptor antagonist D-Ala 7 -Ang-(1-7) blocked the attenuation of the serumstimulated DNA synthesis of SK-LU-1 cells by Ang-(1-7), whereas neither AT 1 nor AT 2 angiotensin receptor subtype antagonists prevented the response to the heptapeptide.…”

Section: An Additional Perspectivementioning

confidence: 95%

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

confidence: 83%

Section: An Additional Perspectivementioning

confidence: 95%

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

2006

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“…The interaction between ACE and ACE2 is demonstrated by the observation that ACE inhibition results in elevation of Ang 1-7 in vivo and blockade of Ang 1-7 with a specific antagonist reverses the antihypertensive effects of lisinopril. 4,6,18 Furthermore, a recent study demonstrated that lentiviral delivery of ACE2 can reverse cardiac hypertrophy in rats, suggesting not only that ACE2 is beneficial, but that manipulation of ACE2 may have therapeutic potential. 19 Direct evidence for ACE2 in the development of hypertensive cardiopathy and kidney disease comes from the ACE2 gene knockout mice.…”

Section: Discussionmentioning

confidence: 99%

Angiotensin II Up-Regulates Angiotensin I-Converting Enzyme (ACE), but Down-Regulates ACE2 via the AT1-ERK/p38 MAP Kinase Pathway

Koka

Huang

Chung

et al. 2008

The American Journal of Pathology

261

258

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The recent discovery of the angiotensin II (Ang II)-breakdown enzyme, angiotensin I converting enzyme (ACE) 2, suggests the importance of Ang II degradation in hypertension. The present study explored the signaling mechanism by which ACE2 is regulated under hypertensive conditions. Real-time PCR and immunohistochemistry showed that ACE2 mRNA and protein expression levels were high, whereas ACE expression levels were moderate in both normal kidney and heart. In contrast, patients with hypertension showed marked ACE up-regulation and ACE2 down-regulation in both hypertensive cardiopathy and, particularly, hypertensive nephropathy. The inhibition of ACE2 expression was shown to be associated with ACE up-regulation and activation of extracellular regulated (ERK)1/2 and p38 mitogen-activated protein (MAP) kinases. In vitro, Ang II was able to upregulate ACE and down-regulate ACE2 in human kidney tubular cells, which were blocked by an angiotensin II (AT)1 receptor antagonist (losartan), but not by an AT2 receptor blocker (PD123319). Furthermore, blockade of ERK1/2 or p38 MAP kinases by either specific inhibitors or a dominant-negative adenovirus was able to abolish Ang II-induced ACE2 down-regulation in human kidney tubular cells. In conclusion, Ang II is able to up-regulate ACE and down-regulate ACE2 expression levels under hypertensive conditions both in vivo and in vitro. The AT1 receptor-mediated ERK/p38 MAP kinase signaling pathway may be a key mechanism by which Ang II down-regulates ACE2 expression, implicating an ACE/ACE2 imbalance in hypertensive cardiovascular and renal damage. The prevalence of hypertension is approximately 30% based on National Health and Nutrition Examination Survey data, 1 making it one of the most important risk factors for cardiovascular disease, the major cause of mortality in the United States.The recent discovery of the angiotensin II (Ang II) breakdown enzyme angiotensin I -converting enzyme (ACE)2 and alternative Ang II-generating pathways such as chymase, in addition to ACE, has increased the complexity of our understanding of Ang II generation and degradation in hypertension. 2,3 ACE2 is a breakdown enzyme responsible for the degradation of Ang II to Angiotensin 1-7 peptide. The later has vasodilatory properties and has its own unique receptor, the Mas receptor. 3 Emerging evidence shows that ACE2 plays an important role in negatively regulating hypertension. In rat models of hypertension, renal ACE2 mRNA and protein are decreased, although this could not be confirmed in human hypertensive nephropathy in a prior study. 4 Further, in rats treated with ACE inhibitors and angiotensin receptor blockers, an increase in local renal ACE2 activity is noted. 5,6 We have shown earlier that ACE is up-regulated in human diabetic nephropathy accompanied with hypertension, a condition associated with high Ang II levels. 7 Taken together, these findings suggest that there may be an alteration in the ACE/ACE2 balance in hypertension in a manner that favors increased Ang II generation (ie, upre...

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“…This raises the hypothesis of there being another isoform of ACE present in the aorta which is inhibited by Lisinopril as well but does not cleave Hippuryl-His-Leu nor does it crossreact with our immunohistochemistry antibody. The local vascular RAS activity in aortic tissue has been demonstrated in rat by Igase et al (2005) and distinguished from that in other vascular beds, namely, carotid arteries. Also, as noted above, in homogenates, in contrast to functional measurement in the aortic rings, the normal vascular (ACEi) on the contractile response to AngI was studied; it showed a shift toward the right in the curves, with subsequently no differences between the conversion from AngI to AngII anymore (d) architecture is destroyed.…”

Section: Described This Polymorphism In Inbred Brownmentioning

confidence: 99%

Differential ACE expression among tissues in allele-specific Wistar rat lines

et al. 2009

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In humans, the insertion/deletion polymorphism in the angiotensin converting enzyme (ACE) gene accounts for half of the variance in plasma ACE activity. The deletion allele is associated with high plasma ACE activity, cardiovascular disease, and renal disease. In rat, a similar association is found between the B and L alleles of a microsatellite marker in the ACE gene. We identified the B/L variation in the Wistar outbred rat and bred two lines homozygous for the two alleles (WU-B and WU-L). ACE activity was measured in serum, heart, kidney, and aorta homogenates. Immunohistochemistry and ACE mRNA expression were performed in heart, kidney, and aortic tissue. Aortic rings were collected and stimulated with AngI, AngII, and AngI with Lisinopril to measure ACE functional activity by vasoconstrictor response. Serum, heart, and kidney ACE activity and kidney mRNA expression were two-fold higher in WU-B. Kidney staining showed a clear difference in tubular ACE expression, with more staining in WU-B. While in aorta ACE activity and mRNA expression was twofold higher in WU-L, functional conversion of AngI was higher in WU-B, indicating either a functional difference in AngI to AngII conversion between the two alleles due to different splicing or the presence of other factors involved in the conversion that are differentially expressed as the result of differences in the ACE alleles. The newly developed WU-B and WU-L lines show tissue-specific differences in ACE expression and activity. This provides an experimental tool to study the pathophysiologic consequences of differences in ACE alleles in renal and cardiovascular disease.

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Angiotensin II AT₁ receptors regulate ACE2 and angiotensin-(1–7) expression in the aorta of spontaneously hypertensive rats

Cited by 199 publications

References 34 publications

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

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

Angiotensin II Up-Regulates Angiotensin I-Converting Enzyme (ACE), but Down-Regulates ACE2 via the AT1-ERK/p38 MAP Kinase Pathway

Differential ACE expression among tissues in allele-specific Wistar rat lines

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Angiotensin II AT1 receptors regulate ACE2 and angiotensin-(1–7) expression in the aorta of spontaneously hypertensive rats

Cited by 199 publications

References 34 publications

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

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

Angiotensin II Up-Regulates Angiotensin I-Converting Enzyme (ACE), but Down-Regulates ACE2 via the AT1-ERK/p38 MAP Kinase Pathway

Differential ACE expression among tissues in allele-specific Wistar rat lines

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Angiotensin II AT₁ receptors regulate ACE2 and angiotensin-(1–7) expression in the aorta of spontaneously hypertensive rats