Renal and Metabolic Clearance of
            <i>N</i>
            -Acetyl-Seryl-Aspartyl-Lysyl-Proline (AcSDKP) During Angiotensin-Converting Enzyme Inhibition in Humans

Azizi, Michel; Ezan, Éric; Reny, Jean-Luc; Wdzieczak‐Bakala, Joanna; Gerineau, Vincent; Ménard, Joël

doi:10.1161/01.hyp.33.3.879

Cited by 44 publications

(30 citation statements)

References 20 publications

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“…19 Although the functional role of exogenous AcSDKP was demonstrated in the myocardium, 7,20 endogenous levels of this peptide in the myocardium had not yet been shown. We show here that cardiac AcSDKP levels in the myocardium of wild-type rats is higher than what has been reported in plasma, suggesting that the myocardium actively generates or traps AcSDKP.…”

Section: Acsdkp Is An Antifibrotic Agentmentioning

confidence: 99%

Increased Myocardial Collagen Content in Transgenic Rats Overexpressing Cardiac Angiotensin-Converting Enzyme Is Related to Enhanced Breakdown of N -Acetyl-Ser-Asp-Lys-Pro and Increased Phosphorylation of Smad2/3

et al. 2004

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Background-Although increased activity of angiotensin-converting enzyme (ACE) has been associated with increased cardiac collagen, no studies to date have established a direct cause-and-effect relation between the two. Methods and Results-We used transgenic rats that overexpress human ACE selectively in the myocardium. Two independent heterozygous transgenic rat lines were studied, one expressing 2 to 3 copies (L1172) and the other expressing 5 to 10 copies (L1173) of the ACE transgene. These rats were normotensive but developed a proportionate increase in myocardial collagen depending on the ACE gene dose (up to 2.5-fold, PϽ0.01), but cardiac angiotensin II levels remained normal, whereas collagen content reversed to control levels on ACE inhibition. To explain these changes, we investigated N-acetyl-Ser-Asp-Lys-Pro (AcSDKP), an alternative substrate that is catabolized exclusively by ACE. Increased cardiac expression of ACE was paralleled by a reciprocal decrease in cardiac AcSDKP and a proportionate increase in phosphorylated Smad2 and Smad3, all of which normalized after both ACE inhibition and AcSDKP infusion. Furthermore, a functional link of this signaling cascade was demonstrated, because AcSDKP inhibited Smad3 phosphorylation in a dose-dependent manner in cultured cardiac fibroblasts and in vivo. Conclusions-Our findings suggest that increased cardiac ACE activity can increase cardiac collagen content by degradation of AcSDKP, an inhibitor of the phosphorylation of transforming growth factor-␤ signaling molecules Smad2 and Smad3. This implies that the antifibrotic effects of ACE inhibitors are mediated in part by increasing cardiac AcSDKP, with subsequent inhibition of Smad 2/3 phosphorylation.

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Section: Acsdkp Is An Antifibrotic Agentmentioning

confidence: 99%

Increased Myocardial Collagen Content in Transgenic Rats Overexpressing Cardiac Angiotensin-Converting Enzyme Is Related to Enhanced Breakdown of N -Acetyl-Ser-Asp-Lys-Pro and Increased Phosphorylation of Smad2/3

et al. 2004

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“…15 The time course evolution of plasma and urinary AcSDKP concentrations were used as very sensitive markers of in vivo inhibition of the N-domain activity. 16 …”

Section: Plasma Ang II Ang I and Acsdkp Determinationsmentioning

confidence: 99%

“…A new substrate for N-domain was designed to monitor easily the N-domain activity. The results obtained were compared with plasma and urinary AcSDKP levels, a reflection of in vivo N-domain inhibition, 16 and with the Ang II/Ang I ratio, an indicator of both N-domain and C-domain activity.…”

Section: Azizi Et Al Inhibition Of Active Sites Of Ace By Omapatrilatmentioning

confidence: 99%

In Vitro and In Vivo Inhibition of the 2 Active Sites of ACE by Omapatrilat, a Vasopeptidase Inhibitor

et al. 2000

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Abstract-The vasopeptidase inhibitor omapatrilat inhibits both neutral endopeptidase and angiotensin-converting enzyme (ACE). The in vitro and in vivo inhibitory potency of omapatrilat and the specific ACE inhibitor fosinopril toward the 2 active sites of ACE (called N-and C-domains) was investigated with the use of 3 substrates: angiotensin I, which is equally cleaved by the 2 ACE domains; hippuryl-histidyl-leucine, specific synthetic substrate of the C-domain in highsalt conditions; and a newly synthesized specific substrate of the N-domain designed by acetylating the lysine residue of AcSDKP. In vitro, omapatrilat was 5 times more potent than fosinoprilat in inhibiting angiotensin I hydrolysis. Omapatrilat inhibited similarly both N-and C-domain hydrolysis, whereas fosinoprilat was slightly more specific for the N-domain. The in vivo selective inhibitory potency of single oral doses of 10 mg omapatrilat and 20 mg fosinopril were investigated in a double-blind, placebo-controlled, cross-over study in 9 mildly sodium-depleted normotensive subjects. In accordance with the in vitro results, fosinopril appeared to be more specific for the N-domain than the C-domain in vivo, since plasma and urine AcSDKP concentrations were significantly higher than those observed with omapatrilat. This study shows that it is possible to assess separately in vitro and in vivo the selectivity of ACE or ACE/neutral endopeptidase inhibitors. A differential selectivity may explain some peculiar properties observed with some ACE inhibitors. Key Words: angiotensin-converting enzyme Ⅲ angiotensin-converting enzyme inhibitors Ⅲ AcSDKP Ⅲ human A ngiotensin-converting enzyme (ACE) has 2 distinct active catalytic sites, hereafter called the N-and C-domains. 1 The 2 domains of ACE have both common and different characteristics. Both sites hydrolyze angiotensin (Ang) I and bradykinin with almost the same catalytic efficiency. 2 The N-domain cleaves specifically 2 physiological substrates, Ang-(1-7) 3 and N-acetyl-seryl-aspartyl-lysylproline (AcSDKP), a hemoregulatory peptide. 4 There is no known specific physiological substrates of the C-domain, but the C-domain activity can be assessed specifically in vitro by the use of the synthetic tripeptide hippuryl-histidyl-leucine (HHL), because its hydrolysis in high chloride concentration depends mostly on this catalytic site. 1 Finally, some ACE inhibitors display different inhibitory potency toward the 2 active sites. 5 For example, captopril appears to be Ϸ16 times more efficient for blocking the N-domain than the C-domain, whereas lisinopril is equally potent toward the 2 active sites. 6 The inhibitory potency of ACE inhibitors toward ACE can be studied with the use of synthetic 7 and physiological substrates 8 or with the use of a competitive assay against radiolabeled ACE inhibitors. 9 In addition, it is possible to explore the characteristics of the inhibitors toward the 2 ACE domains separately by selecting appropriate substrates and markers. Such studies will allow us to specifically relate t...

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“…Of these, AcSDKP is of particular interest because of its role in hematopoiesis and tissue fibrosis, suggesting possible additional applications of ACE inhibitors. 4 N domain-mediated cleavage of AcSDKP has been shown to be relevant in vivo by the observation that plasma levels increase with N domain-selective, but not C domain-selective, ACE inhibitors, 5 and in studies with N-domain knockout mice. 6 …”

Section: Introductionmentioning

confidence: 99%

C domain-selective inhibition of angiotensin-converting enzyme

Ehlers

Abrie

Sturrock

2013

J Renin Angiotensin Aldosterone Syst

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Renal and Metabolic Clearance of N -Acetyl-Seryl-Aspartyl-Lysyl-Proline (AcSDKP) During Angiotensin-Converting Enzyme Inhibition in Humans

Cited by 44 publications

References 20 publications

Increased Myocardial Collagen Content in Transgenic Rats Overexpressing Cardiac Angiotensin-Converting Enzyme Is Related to Enhanced Breakdown of N -Acetyl-Ser-Asp-Lys-Pro and Increased Phosphorylation of Smad2/3

Increased Myocardial Collagen Content in Transgenic Rats Overexpressing Cardiac Angiotensin-Converting Enzyme Is Related to Enhanced Breakdown of N -Acetyl-Ser-Asp-Lys-Pro and Increased Phosphorylation of Smad2/3

In Vitro and In Vivo Inhibition of the 2 Active Sites of ACE by Omapatrilat, a Vasopeptidase Inhibitor

C domain-selective inhibition of angiotensin-converting enzyme

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