Acute angiotensin-converting enzyme inhibition increases the plasma level of the natural stem cell regulator N-acetyl-seryl-aspartyl-lysyl-proline.

Azizi, Michel; Rousseau, Anne; Ezan, Éric; Guyene, Thanh‐Tam; Michelet, Stéphanie; Grognet, Jean‐Marc; Lenfant, Maryse; Corvol, Pierre; Ménard, Joël

doi:10.1172/jci118484

Cited by 306 publications

(253 citation statements)

References 27 publications

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“…Although the amino-terminal domain does cleave AcSDKP in vivo (9), the physiological significance of the two catalytic sites is not at present known.…”

Section: Introductionmentioning

confidence: 99%

The critical role of tissue angiotensin-converting enzyme as revealed by gene targeting in mice.

Esther¹,

Marino²,

Howard³

et al. 1997

J. Clin. Invest.

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266

211

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Angiotensin-converting enzyme (ACE) generates the vasoconstrictor angiotensin II, which plays a critical role in maintenance of blood pressure in mammals. Although significant ACE activity is found in plasma, the majority of the enzyme is bound to tissues such as the vascular endothelium. We used targeted homologous recombination to create mice expressing a form of ACE that lacks the COOH-terminal half of the molecule. This modified ACE protein is catalytically active but entirely secreted from cells. Mice that express only this modified ACE have significant plasma ACE activity but no tissue-bound enzyme. These animals have low blood pressure, renal vascular thickening, and a urine concentrating defect. The phenotype is very similar to that of completely ACE-deficient mice previously reported, except that the renal pathology is less severe. These studies strongly support the concept that the tissue-bound ACE is essential to the control of blood pressure and the structure and function of the kidney. ( J. Clin. Invest. 1997. 99:2375-2385.)

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“…Although the amino-terminal domain does cleave AcSDKP in vivo (9), the physiological significance of the two catalytic sites is not at present known.…”

Section: Introductionmentioning

confidence: 99%

The critical role of tissue angiotensin-converting enzyme as revealed by gene targeting in mice.

Esther¹,

Marino²,

Howard³

et al. 1997

J. Clin. Invest.

Self Cite

266

211

View full text Add to dashboard Cite

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“…Moreover, ACE has recently been implicated in the hydrolysis in vivo of the tetrapeptide Ac-Ser-Asp-Lys-Pro, which modulates hematopoietic stem cell proliferation by preventing their recruitment into the S phase (23). The acute administration of captopril, an ACE inhibitor, produces a 7-fold increase in the plasma concentration of AcSer-Asp-Lys-Pro in normal volunteers, thus demonstrating the importance of ACE in the metabolism of this substrate (24).…”

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confidence: 99%

Novel Natural Peptide Substrates for Endopeptidase 24.15, Neurolysin, and Angiotensin-converting Enzyme

Rioli

Gozzo²,

Heimann

et al. 2003

Journal of Biological Chemistry

159

165

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The hemoglobin ␣-chain fragment PVNFKFLSH, which we have named hemopressin, produced dose-dependent hypotension in anesthetized rats, starting at 0.001 g/kg. The hypotensive effect of the peptide was potentiated by enalapril only at the lowest peptide dose. These results suggest a role for hemopressin as a vasoactive substance in vivo. The identification of these putative intracellular substrates for ep24.15 and ep24.16 is an important step toward the elucidation of the role of these enzymes within cells. Endopeptidase EC 3.4.24.15 (ep24.15; also referred to as thimet oligopeptidase) and endopeptidase EC 3. 4.24.16 (ep24.16; also referred to as neurolysin) were initially detected in and purified from rat brain homogenates (1, 2). The cloned rat brain ep24.16 (3) showed 80% similarity and 63% identity with the previously cloned rat testis ep24.15 (4). Both peptidases share most of their natural substrates, including bradykinin, neurotensin, opioids, angiotensin I, and gonadotrophinreleasing hormone (5, 6

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“…The plasma levels of Ac-SDKP were shown to be increased by fivefold after the administration of ACE-I in humans (13). Ac-SDKP was shown to suppress the proliferation of renal fibroblasts (14) and to inhibit DNA synthesis as well as collagen deposition in cardiac fibroblasts (15).…”

mentioning

confidence: 99%

N-Acetyl-Seryl-Aspartyl-Lysyl-Proline Inhibits TGF-β–Mediated Plasminogen Activator Inhibitor-1 Expression via Inhibition of Smad Pathway in Human Mesangial Cells

Kanasaki

Koya

Sugimoto

et al. 2003

Journal of the American Society of Nephrology

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Abstract. Recent large clinical trials indicate that angiotensinconverting enzyme inhibitors (ACE-I) attenuate the detrimental outcome of progressive renal disease. The hemoregulatory tetrapeptide N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP, AcSDKP) is hydrolyzed by ACE, and plasma Ac-SDKP level is increased by fivefold after treatment with ACE-I. Ac-SDKP was found to ameliorate cardiac and renal fibrosis in hypertensive animal models. However, the molecular mechanisms by which Ac-SDKP mediates anti-fibrotic effects remain unclear. This study is an examination of the interaction between Ac-SDKP and transforming growth factor-␤ (TGF-␤), one of the key cytokines in the progression of renal disease, in human mesangial cells. Ac-SDKP inhibited TGF-␤1-induced plasminogen activator inhibitor-1 (PAI-1) and alpha2 (I) collagen mRNA. Ac-SDKP suppressed not only TGF-␤1-induced Smad2 phosphorylation at Ser-465/467 in a dose-dependent manner, but also the nuclear accumulation of receptor-regulated Smads (R-Smad), Smad2 and Smad3. As expected, Ac-SDKP inhibited TGF-␤-responsive Smad-dependent luciferase reporters, 3TP-luc and 4xSBE-luc. Immunofluorescence analysis revealed that the inhibitory Smad, Smad7, was exported to the cytoplasm from the nucleus by the treatment with Ac-SDKP. These findings provide novel evidence that Ac-SDKP inhibits TGF-␤ signal transduction through the suppression of R-Smad activation via nuclear export of Smad7, highlighting an alternative mechanism involved in the reno-protective efficacy of ACE-I.

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Acute angiotensin-converting enzyme inhibition increases the plasma level of the natural stem cell regulator N-acetyl-seryl-aspartyl-lysyl-proline.

Cited by 306 publications

References 27 publications

The critical role of tissue angiotensin-converting enzyme as revealed by gene targeting in mice.

The critical role of tissue angiotensin-converting enzyme as revealed by gene targeting in mice.

Novel Natural Peptide Substrates for Endopeptidase 24.15, Neurolysin, and Angiotensin-converting Enzyme

N-Acetyl-Seryl-Aspartyl-Lysyl-Proline Inhibits TGF-β–Mediated Plasminogen Activator Inhibitor-1 Expression via Inhibition of Smad Pathway in Human Mesangial Cells

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