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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:297.)
© 2007 American Heart Association, Inc.

Vascular Biology

Mass-Spectrometric Identification of a Novel Angiotensin Peptide in Human Plasma

Vera Jankowski; Raymond Vanholder; Markus van der Giet; Markus Tölle; Sevil Karadogan; Johan Gobom; Jens Furkert; Alexander Oksche; Eberhard Krause; Thi Nguyet Anh Tran; Martin Tepel; Mirjam Schuchardt; Hartmut Schlüter; Annette Wiedon; Michael Beyermann; Michael Bader; Mihail Todiras; Walter Zidek; Joachim Jankowski

From the Charité-Universitätsmedizin Berlin (V.J., M.v.d.G., M.Tölle, S.K., M.Tepel, M.S., H.S., A.W., W.Z., J.J.), Campus Benjamin Franklin Medizinische Klinik IV, Germany; Nephrology Section (R.V.), Department of Internal Medicine, University Hospital, Gent, Belgium; Max Planck Institute for Molecular Genetics (J.G.), Berlin, Germany; Charité-Universitätsmedizin Berlin (J.F., A.O.), Institut für Pharmakologie, Germany; Forschungsinstitut für Molekulare Pharmakologie (E.K., M.Beyermann, M.T.), Berlin, Germany; and Max-Delbrück-Center for Molecular Medicine (M.Bader), Berlin, Germany.

Correspondence to Priv.-Doz. Dr J. Jankowski, Charité Universitätsmedizin Berlin, Campus Benjamin Franklin Med Klinik IV, Hindenburgdamm 30, 12200 Berlin, Germany. E-mail Joachim.Jankowski{at}charite.de

Objective— Angiotensin peptides play a central role in cardiovascular physiology and pathology. Among these peptides, angiotensin II (Ang II) has been investigated most intensively. However, further angiotensin peptides such as Ang 1-7, Ang III, and Ang IV also contribute to vascular regulation, and may elicit additional, different, or even opposite effects to Ang II. Here, we describe a novel Ang II-related, strong vasoconstrictive substance in plasma from healthy humans and end-stage renal failure patients.

Methods and Results— Chromatographic purification and structural analysis by matrix-assisted laser desorption/ionisation time-of-flight/time-of-flight (MALDI-TOF/TOF) revealed an angiotensin octapeptide with the sequence Ala-Arg-Val-Tyr-Ile-His-Pro-Phe, which differs from Ang II in Ala¹ instead of Asp¹. Des[Asp¹]-[Ala¹]-Ang II, in the following named Angiotensin A (Ang A), is most likely generated enzymatically. In the presence of mononuclear leukocytes, Ang II is converted to Ang A by decarboxylation of Asp¹. Ang A has the same affinity to the AT₁ receptor as Ang II, but a higher affinity to the AT₂ receptor. In the isolated perfused rat kidney, Ang A revealed a smaller vasoconstrictive effect than Ang II, which was not modified in the presence of the AT2 receptor antagonist PD 123319, suggesting a lower intrinsic activity at the AT₁ receptor. Ang II and Ang A concentrations in plasma of healthy subjects and end-stage renal failure patients were determined by matrix-assisted laser desorption/ionisation mass-analysis, because conventional enzyme immunoassay for Ang II quantification did not distinguish between Ang II and Ang A. In healthy subjects, Ang A concentrations were less than 20% of the Ang II concentrations, but the ratio Ang A / Ang II was higher in end-stage renal failure patients.

Conclusion— Ang A is a novel human strong vasoconstrictive angiotensin-derived peptide, most likely generated by enzymatic transformation through mononuclear leukocyte-derived aspartate decarboxylase. Plasma Ang A concentration is increased in end-stage renal failure. Because of its stronger agonism at the AT₂ receptor, Ang A may modulate the harmful effects of Ang II.

In this study, a new angiotensin-peptide of human plasma is described, which is characterized as a strong AT₂-receptor agonist.

Key Words: mass-spectrometry • vasoconstriction • angiotensin-peptide • human plasma

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