Increased angiotensin-I converting enzyme gene expression in the failing human heart. Quantification by competitive RNA polymerase chain reaction.

Studer, Rebecca K.; Reinecke, Hans; Müller, Bárbara; Holtz, J.; Just, Hanjörg; Drexler, Helmut

doi:10.1172/jci117322

Cited by 187 publications

(76 citation statements)

References 55 publications

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“…Housekeeping gene GAPDH was used as an internal standard. The primers used in this study are as follows: ACE forward 5Ј-GCAAG-GAGGCAGGCTATGAG-3Ј and reverse 5Ј-CGGGTA-AAACTGGAGGATGG-3Ј 16 ; ACE2 forward 5Ј-CATTGGAG-CAAGTGTTGGATCTT-3Ј and reverse 5Ј-GAGCTAATGC-ATGCCATTCTCA-3Ј; GAPDH forward 5Ј-CAATGACCCCT-TCATTGACC-3Ј and reverse 5Ј-GTTCACACCCATGACG-AACATG.…”

Section: Reverse Transcription and Real-time Pcrmentioning

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

259

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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Section: Reverse Transcription and Real-time Pcrmentioning

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

259

258

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“…4,5 ACE2 does not act on bradykinins and its activity is not inhibited by ACE inhibitors. 2 Although a significant activation of the RAS system occurs after myocardial infarction, 6 -10 the role of ACE2 and its main products [Ang- (1)(2)(3)(4)(5)(6)(7)(8)(9) and Ang-(1-7)] are still poorly understood. The importance of ACE2 in regulating cardiac function has been implicated by the phenotype of the ACE2 knockout mouse, showing left ventricular dilation, impaired contractility with upregulation of hypoxia-induced genes in the heart, suggesting a link to myocardial ischemia.…”

mentioning

confidence: 99%

Enalapril Attenuates Downregulation of Angiotensin-Converting Enzyme 2 in the Late Phase of Ventricular Dysfunction in Myocardial Infarcted Rat

et al. 2006

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Abstract-The early and long-term effects of coronary artery ligation on the plasma and left ventricular angiotensinconverting enzyme (ACE and ACE2) activities, ACE and ACE2 mRNA levels, circulating angiotensin (Ang) levels [Ang I, Ang-(1-7), Ang-(1-9), and Ang II], and cardiac function were evaluated 1 and 8 weeks after experimental myocardial infarction in adult Sprague Dawley rats. Sham-operated rats were used as controls. Coronary artery ligation caused myocardial infarction, hypertrophy, and dysfunction 8 weeks after surgery. At week 1, circulating Ang II and Ang-(1-9) levels as well as left ventricular and plasma ACE and ACE2 activities increased in myocardial-infarcted rats as compared with controls. At 8 weeks post-myocardial infarction, circulating ACE activity, ACE mRNA levels, and Ang II levels remained higher, but plasma and left ventricular ACE2 activities and mRNA levels and circulating levels of Ang-(1-9) were lower than in controls. No changes in plasma Ang-(1-7) levels were observed at any time. Enalapril prevented cardiac hypertrophy and dysfunction as well as the changes in left ventricular ACE, left ventricular and plasmatic ACE2, and circulating levels of Ang II and Ang-(1-9) after 8 weeks postinfarction. Thus, the decrease in ACE2 expression and activity and circulating Ang-(1-9) levels in late ventricular dysfunction post-myocardial infarction were prevented with enalapril. These findings suggest that in this second arm of the renin-angiotensin system, ACE2 may act through Ang-(1-9), rather than Ang-(1-7), as a counterregulator of the first arm, where ACE catalyzes the formation of Ang II. Key Words: angiotensin-converting enzyme Ⅲ myocardial infarction Ⅲ renin-angiotensin system Ⅲ remodeling Ⅲ cardiac function T he renin-angiotensin system (RAS) is a more complex system than originally thought. A new angiotensin-converting enzyme (ACE), ACE2, has been recently identified as a homologue of ACE. 1 ACE2 is also a metalloprotease consisting of 805 amino acids with a considerable degree of homology to ACE (40% identity and 61% similarity). 2,3 ACE2 contains a single zinc-binding domain and is a carboxypeptidase, unlike somatic ACE, which contains 2 zinc-binding domains and is a dipeptidyl carboxypeptidase. 2 Both ACE2 and ACE are bound to the plasma membrane and must be cleaved to release the soluble enzyme. 2 Their cellular and tissue distributions are also different, in that ACE is expressed in the endothelium throughout the vasculature, whereas ACE2 is distributed to most tissues, including to the heart and kidney. 3 Analyses in vitro have shown that ACE2 cleaves angiotensin (Ang) I to Ang-(1-9), which is then cleaved by ACE to Ang-(1-7). However, ACE2 also cleaves Ang II to form Ang-(1-7). Because Ang-(1-7) is a potent vasodepressor peptide, its actions could counterbalance the vasopressor effect of Ang II. 4,5 ACE2 does not act on bradykinins and its activity is not inhibited by ACE inhibitors. 2 Although a significant activation of the RAS system occurs after myocardial infarction, 6 -10 ...

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“…7 Increased expression of both cardiac renin mRNA and cardiac angiotensinogen mRNA are seen under conditions of experimental chronic pressure overload in rats. 8,9 Expression of the ACE has also been demonstrated to be upregulated within the myocardium of rats with pressure overload induced LVH. [8][9][10][11] These findings suggest that increased expression of ACE in the presence of increased local production of renin and angiotensinogen produce increases in angiotensin II, as a response to pressure overload or damage, in the left ventricle.…”

Section: Left Ventricular Hypertrophymentioning

confidence: 99%

“…8,9 Expression of the ACE has also been demonstrated to be upregulated within the myocardium of rats with pressure overload induced LVH. [8][9][10][11] These findings suggest that increased expression of ACE in the presence of increased local production of renin and angiotensinogen produce increases in angiotensin II, as a response to pressure overload or damage, in the left ventricle. 12,13 This activation of the cardiac renin-angiotensin system occurs independently of systemic angiotensin II generation.…”

Section: Left Ventricular Hypertrophymentioning

confidence: 99%

ACE inhibition in aortic stenosis: dangerous medicine or golden opportunity?

Routledge

Townend

2001

J Hum Hypertens

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Conventionally angiotensin-converting enzyme (ACE) inhibitors are contraindicated in patients with aortic stenosis. Abundant evidence is now available showing that angiotensin II has a central role in the development of left ventricular hypertrophy (LVH), myocardial contractile failure and diastolic dysfunction in response to pressure overload. In animal models, ACE inhibitors have been shown to attenuate these pathological responses. In humans there is no such evidence available, however uncontrolled studies have shown that

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Increased angiotensin-I converting enzyme gene expression in the failing human heart. Quantification by competitive RNA polymerase chain reaction.

Cited by 187 publications

References 55 publications

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

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

Enalapril Attenuates Downregulation of Angiotensin-Converting Enzyme 2 in the Late Phase of Ventricular Dysfunction in Myocardial Infarcted Rat

ACE inhibition in aortic stenosis: dangerous medicine or golden opportunity?

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