title: Identification of the Vasoconstriction-Inhibiting Factor (VIF), a Potent Endogenous Cofactor of Angiotensin II Acting on the Angiotensin II Type 2 Receptor.
abstract: BACKGROUND
  The renin-angiotensin system and especially the angiotensin peptides play a central role in blood pressure regulation. Here, we hypothesize that an as-yet unknown peptide is involved in the action of angiotensin II modulating the vasoregulatory effects as a cofactor.
  
  
  RESULTS
  The peptide with vasodilatory properties was isolated from adrenal glands chromatographically. The effects of this peptide were evaluated in vitro and in vivo, and the receptor affinity was analyzed. The plasma concentration in humans was quantified in patients with chronic kidney disease, patients with heart failure, and healthy control subjects. The amino acid sequence of the peptide from bovine adrenal glands was HSSYEDELSEVL EKPNDQAE PKEVTEEVSSKDAAE, which is a degradation product of chromogranin A. The sequence of the peptide isolated from human plasma was HSGFEDELSEVLENQSSQAELKEAVEEPSSKDVME. Both peptides diminished significantly the vasoconstrictive effect of angiotensin II in vitro. Therefore, we named the peptide vasoconstriction-inhibiting factor (VIF). The vasoregulatory effects of VIF are mediated by the angiotensin II type 2 receptor. VIF impairs angiotensin II-induced phosphorylation of the p38 mitogen-activated protein kinase pathway but not of extracellular-regulated kinase 1/2. The vasodilatory effects were confirmed in vivo. The plasma concentration was significantly increased in renal patients and patients with heart failure.
  
  
  CONCLUSIONS
  VIF is a vasoregulatory peptide that modulates the vasoconstrictive effects of angiotensin II by acting on the angiotensin II type 2 receptor. It is likely that the increase in VIF may serve as a counterregulatory effect to defend against hypertension. The identification of this target may help us to understand the pathophysiology of renal and heart failure and may form a basis for the development of new strategies for the prevention and treatment of cardiovascular disease.
authors: From Charité-Universitätsmedizin Berlin, Medizinische Klinik IV, Berlin, Germany (S.S., W.Z.); Universitätsklinikum RWTH Aachen, Institute of Molecular Cardiovascular Research, Aachen, Germany (S.S., V.J., Y.A., E.L., M.S., J.J.); Charité-Universitätsmedizin Berlin, Institute of Vegetative Physiology, Berlin, Germany (P.W., F.B.M.); Nefrology Service, IMIBIC, Reina Sofia University Hospital, University of Cordoba, Spain (A.R.-B., C.P.-M., M.R., J.R.M.-C.); University Hospital Essen, Department of Nephrology, University of Duisburg-Essen, Essen, Germany (H.B.); University Hospital Aachen, RWTH Aachen, Department of Internal Medicine I-Cardiology, Aachen, Germany (N.M.); and Medical University of Vienna, Center for Medical Statistics, Informatics and Intelligent Systems, Section for Clinical Biometrics, Vienna, Austria (G.H.).
authors: Silvia
authors: S
authors: Salem
authors: From Charité-Universitätsmedizin Berlin, Medizinische Klinik IV, Berlin, Germany (S.S., W.Z.); Universitätsklinikum RWTH Aachen, Institute of Molecular Cardiovascular Research, Aachen, Germany (S.S., V.J., Y.A., E.L., M.S., J.J.); Charité-Universitätsmedizin Berlin, Institute of Vegetative Physiology, Berlin, Germany (P.W., F.B.M.); Nefrology Service, IMIBIC, Reina Sofia University Hospital, University of Cordoba, Spain (A.R.-B., C.P.-M., M.R., J.R.M.-C.); University Hospital Essen, Department of Nephrology, University of Duisburg-Essen, Essen, Germany (H.B.); University Hospital Aachen, RWTH Aachen, Department of Internal Medicine I-Cardiology, Aachen, Germany (N.M.); and Medical University of Vienna, Center for Medical Statistics, Informatics and Intelligent Systems, Section for Clinical Biometrics, Vienna, Austria (G.H.).
authors: Vera
authors: V
authors: Jankowski
authors: From Charité-Universitätsmedizin Berlin, Medizinische Klinik IV, Berlin, Germany (S.S., W.Z.); Universitätsklinikum RWTH Aachen, Institute of Molecular Cardiovascular Research, Aachen, Germany (S.S., V.J., Y.A., E.L., M.S., J.J.); Charité-Universitätsmedizin Berlin, Institute of Vegetative Physiology, Berlin, Germany (P.W., F.B.M.); Nefrology Service, IMIBIC, Reina Sofia University Hospital, University of Cordoba, Spain (A.R.-B., C.P.-M., M.R., J.R.M.-C.); University Hospital Essen, Department of Nephrology, University of Duisburg-Essen, Essen, Germany (H.B.); University Hospital Aachen, RWTH Aachen, Department of Internal Medicine I-Cardiology, Aachen, Germany (N.M.); and Medical University of Vienna, Center for Medical Statistics, Informatics and Intelligent Systems, Section for Clinical Biometrics, Vienna, Austria (G.H.).
authors: Yaw
authors: Y
authors: Asare
authors: From Charité-Universitätsmedizin Berlin, Medizinische Klinik IV, Berlin, Germany (S.S., W.Z.); Universitätsklinikum RWTH Aachen, Institute of Molecular Cardiovascular Research, Aachen, Germany (S.S., V.J., Y.A., E.L., M.S., J.J.); Charité-Universitätsmedizin Berlin, Institute of Vegetative Physiology, Berlin, Germany (P.W., F.B.M.); Nefrology Service, IMIBIC, Reina Sofia University Hospital, University of Cordoba, Spain (A.R.-B., C.P.-M., M.R., J.R.M.-C.); University Hospital Essen, Department of Nephrology, University of Duisburg-Essen, Essen, Germany (H.B.); University Hospital Aachen, RWTH Aachen, Department of Internal Medicine I-Cardiology, Aachen, Germany (N.M.); and Medical University of Vienna, Center for Medical Statistics, Informatics and Intelligent Systems, Section for Clinical Biometrics, Vienna, Austria (G.H.).
authors: Elisa
authors: E
authors: Liehn
authors: From Charité-Universitätsmedizin Berlin, Medizinische Klinik IV, Berlin, Germany (S.S., W.Z.); Universitätsklinikum RWTH Aachen, Institute of Molecular Cardiovascular Research, Aachen, Germany (S.S., V.J., Y.A., E.L., M.S., J.J.); Charité-Universitätsmedizin Berlin, Institute of Vegetative Physiology, Berlin, Germany (P.W., F.B.M.); Nefrology Service, IMIBIC, Reina Sofia University Hospital, University of Cordoba, Spain (A.R.-B., C.P.-M., M.R., J.R.M.-C.); University Hospital Essen, Department of Nephrology, University of Duisburg-Essen, Essen, Germany (H.B.); University Hospital Aachen, RWTH Aachen, Department of Internal Medicine I-Cardiology, Aachen, Germany (N.M.); and Medical University of Vienna, Center for Medical Statistics, Informatics and Intelligent Systems, Section for Clinical Biometrics, Vienna, Austria (G.H.).
authors: Pia
authors: P
authors: Welker
authors: From Charité-Universitätsmedizin Berlin, Medizinische Klinik IV, Berlin, Germany (S.S., W.Z.); Universitätsklinikum RWTH Aachen, Institute of Molecular Cardiovascular Research, Aachen, Germany (S.S., V.J., Y.A., E.L., M.S., J.J.); Charité-Universitätsmedizin Berlin, Institute of Vegetative Physiology, Berlin, Germany (P.W., F.B.M.); Nefrology Service, IMIBIC, Reina Sofia University Hospital, University of Cordoba, Spain (A.R.-B., C.P.-M., M.R., J.R.M.-C.); University Hospital Essen, Department of Nephrology, University of Duisburg-Essen, Essen, Germany (H.B.); University Hospital Aachen, RWTH Aachen, Department of Internal Medicine I-Cardiology, Aachen, Germany (N.M.); and Medical University of Vienna, Center for Medical Statistics, Informatics and Intelligent Systems, Section for Clinical Biometrics, Vienna, Austria (G.H.).
authors: Ana
authors: A
authors: Raya-Bermudez
authors: From Charité-Universitätsmedizin Berlin, Medizinische Klinik IV, Berlin, Germany (S.S., W.Z.); Universitätsklinikum RWTH Aachen, Institute of Molecular Cardiovascular Research, Aachen, Germany (S.S., V.J., Y.A., E.L., M.S., J.J.); Charité-Universitätsmedizin Berlin, Institute of Vegetative Physiology, Berlin, Germany (P.W., F.B.M.); Nefrology Service, IMIBIC, Reina Sofia University Hospital, University of Cordoba, Spain (A.R.-B., C.P.-M., M.R., J.R.M.-C.); University Hospital Essen, Department of Nephrology, University of Duisburg-Essen, Essen, Germany (H.B.); University Hospital Aachen, RWTH Aachen, Department of Internal Medicine I-Cardiology, Aachen, Germany (N.M.); and Medical University of Vienna, Center for Medical Statistics, Informatics and Intelligent Systems, Section for Clinical Biometrics, Vienna, Austria (G.H.).
authors: Carmen
authors: C
authors: Pineda-Martos
authors: From Charité-Universitätsmedizin Berlin, Medizinische Klinik IV, Berlin, Germany (S.S., W.Z.); Universitätsklinikum RWTH Aachen, Institute of Molecular Cardiovascular Research, Aachen, Germany (S.S., V.J., Y.A., E.L., M.S., J.J.); Charité-Universitätsmedizin Berlin, Institute of Vegetative Physiology, Berlin, Germany (P.W., F.B.M.); Nefrology Service, IMIBIC, Reina Sofia University Hospital, University of Cordoba, Spain (A.R.-B., C.P.-M., M.R., J.R.M.-C.); University Hospital Essen, Department of Nephrology, University of Duisburg-Essen, Essen, Germany (H.B.); University Hospital Aachen, RWTH Aachen, Department of Internal Medicine I-Cardiology, Aachen, Germany (N.M.); and Medical University of Vienna, Center for Medical Statistics, Informatics and Intelligent Systems, Section for Clinical Biometrics, Vienna, Austria (G.H.).
authors: Mariano
authors: M
authors: Rodriguez
authors: From Charité-Universitätsmedizin Berlin, Medizinische Klinik IV, Berlin, Germany (S.S., W.Z.); Universitätsklinikum RWTH Aachen, Institute of Molecular Cardiovascular Research, Aachen, Germany (S.S., V.J., Y.A., E.L., M.S., J.J.); Charité-Universitätsmedizin Berlin, Institute of Vegetative Physiology, Berlin, Germany (P.W., F.B.M.); Nefrology Service, IMIBIC, Reina Sofia University Hospital, University of Cordoba, Spain (A.R.-B., C.P.-M., M.R., J.R.M.-C.); University Hospital Essen, Department of Nephrology, University of Duisburg-Essen, Essen, Germany (H.B.); University Hospital Aachen, RWTH Aachen, Department of Internal Medicine I-Cardiology, Aachen, Germany (N.M.); and Medical University of Vienna, Center for Medical Statistics, Informatics and Intelligent Systems, Section for Clinical Biometrics, Vienna, Austria (G.H.).
authors: Juan Rafael
authors: JR
authors: Muñoz-Castañeda
authors: From Charité-Universitätsmedizin Berlin, Medizinische Klinik IV, Berlin, Germany (S.S., W.Z.); Universitätsklinikum RWTH Aachen, Institute of Molecular Cardiovascular Research, Aachen, Germany (S.S., V.J., Y.A., E.L., M.S., J.J.); Charité-Universitätsmedizin Berlin, Institute of Vegetative Physiology, Berlin, Germany (P.W., F.B.M.); Nefrology Service, IMIBIC, Reina Sofia University Hospital, University of Cordoba, Spain (A.R.-B., C.P.-M., M.R., J.R.M.-C.); University Hospital Essen, Department of Nephrology, University of Duisburg-Essen, Essen, Germany (H.B.); University Hospital Aachen, RWTH Aachen, Department of Internal Medicine I-Cardiology, Aachen, Germany (N.M.); and Medical University of Vienna, Center for Medical Statistics, Informatics and Intelligent Systems, Section for Clinical Biometrics, Vienna, Austria (G.H.).
authors: Heike
authors: H
authors: Bruck
authors: From Charité-Universitätsmedizin Berlin, Medizinische Klinik IV, Berlin, Germany (S.S., W.Z.); Universitätsklinikum RWTH Aachen, Institute of Molecular Cardiovascular Research, Aachen, Germany (S.S., V.J., Y.A., E.L., M.S., J.J.); Charité-Universitätsmedizin Berlin, Institute of Vegetative Physiology, Berlin, Germany (P.W., F.B.M.); Nefrology Service, IMIBIC, Reina Sofia University Hospital, University of Cordoba, Spain (A.R.-B., C.P.-M., M.R., J.R.M.-C.); University Hospital Essen, Department of Nephrology, University of Duisburg-Essen, Essen, Germany (H.B.); University Hospital Aachen, RWTH Aachen, Department of Internal Medicine I-Cardiology, Aachen, Germany (N.M.); and Medical University of Vienna, Center for Medical Statistics, Informatics and Intelligent Systems, Section for Clinical Biometrics, Vienna, Austria (G.H.).
authors: Nikolaus
authors: N
authors: Marx
authors: From Charité-Universitätsmedizin Berlin, Medizinische Klinik IV, Berlin, Germany (S.S., W.Z.); Universitätsklinikum RWTH Aachen, Institute of Molecular Cardiovascular Research, Aachen, Germany (S.S., V.J., Y.A., E.L., M.S., J.J.); Charité-Universitätsmedizin Berlin, Institute of Vegetative Physiology, Berlin, Germany (P.W., F.B.M.); Nefrology Service, IMIBIC, Reina Sofia University Hospital, University of Cordoba, Spain (A.R.-B., C.P.-M., M.R., J.R.M.-C.); University Hospital Essen, Department of Nephrology, University of Duisburg-Essen, Essen, Germany (H.B.); University Hospital Aachen, RWTH Aachen, Department of Internal Medicine I-Cardiology, Aachen, Germany (N.M.); and Medical University of Vienna, Center for Medical Statistics, Informatics and Intelligent Systems, Section for Clinical Biometrics, Vienna, Austria (G.H.).
authors: Fernanda B
authors: FB
authors: Machado
authors: From Charité-Universitätsmedizin Berlin, Medizinische Klinik IV, Berlin, Germany (S.S., W.Z.); Universitätsklinikum RWTH Aachen, Institute of Molecular Cardiovascular Research, Aachen, Germany (S.S., V.J., Y.A., E.L., M.S., J.J.); Charité-Universitätsmedizin Berlin, Institute of Vegetative Physiology, Berlin, Germany (P.W., F.B.M.); Nefrology Service, IMIBIC, Reina Sofia University Hospital, University of Cordoba, Spain (A.R.-B., C.P.-M., M.R., J.R.M.-C.); University Hospital Essen, Department of Nephrology, University of Duisburg-Essen, Essen, Germany (H.B.); University Hospital Aachen, RWTH Aachen, Department of Internal Medicine I-Cardiology, Aachen, Germany (N.M.); and Medical University of Vienna, Center for Medical Statistics, Informatics and Intelligent Systems, Section for Clinical Biometrics, Vienna, Austria (G.H.).
authors: Mareike
authors: M
authors: Staudt
authors: From Charité-Universitätsmedizin Berlin, Medizinische Klinik IV, Berlin, Germany (S.S., W.Z.); Universitätsklinikum RWTH Aachen, Institute of Molecular Cardiovascular Research, Aachen, Germany (S.S., V.J., Y.A., E.L., M.S., J.J.); Charité-Universitätsmedizin Berlin, Institute of Vegetative Physiology, Berlin, Germany (P.W., F.B.M.); Nefrology Service, IMIBIC, Reina Sofia University Hospital, University of Cordoba, Spain (A.R.-B., C.P.-M., M.R., J.R.M.-C.); University Hospital Essen, Department of Nephrology, University of Duisburg-Essen, Essen, Germany (H.B.); University Hospital Aachen, RWTH Aachen, Department of Internal Medicine I-Cardiology, Aachen, Germany (N.M.); and Medical University of Vienna, Center for Medical Statistics, Informatics and Intelligent Systems, Section for Clinical Biometrics, Vienna, Austria (G.H.).
authors: Georg
authors: G
authors: Heinze
authors: From Charité-Universitätsmedizin Berlin, Medizinische Klinik IV, Berlin, Germany (S.S., W.Z.); Universitätsklinikum RWTH Aachen, Institute of Molecular Cardiovascular Research, Aachen, Germany (S.S., V.J., Y.A., E.L., M.S., J.J.); Charité-Universitätsmedizin Berlin, Institute of Vegetative Physiology, Berlin, Germany (P.W., F.B.M.); Nefrology Service, IMIBIC, Reina Sofia University Hospital, University of Cordoba, Spain (A.R.-B., C.P.-M., M.R., J.R.M.-C.); University Hospital Essen, Department of Nephrology, University of Duisburg-Essen, Essen, Germany (H.B.); University Hospital Aachen, RWTH Aachen, Department of Internal Medicine I-Cardiology, Aachen, Germany (N.M.); and Medical University of Vienna, Center for Medical Statistics, Informatics and Intelligent Systems, Section for Clinical Biometrics, Vienna, Austria (G.H.).
authors: Walter
authors: W
authors: Zidek
authors: From Charité-Universitätsmedizin Berlin, Medizinische Klinik IV, Berlin, Germany (S.S., W.Z.); Universitätsklinikum RWTH Aachen, Institute of Molecular Cardiovascular Research, Aachen, Germany (S.S., V.J., Y.A., E.L., M.S., J.J.); Charité-Universitätsmedizin Berlin, Institute of Vegetative Physiology, Berlin, Germany (P.W., F.B.M.); Nefrology Service, IMIBIC, Reina Sofia University Hospital, University of Cordoba, Spain (A.R.-B., C.P.-M., M.R., J.R.M.-C.); University Hospital Essen, Department of Nephrology, University of Duisburg-Essen, Essen, Germany (H.B.); University Hospital Aachen, RWTH Aachen, Department of Internal Medicine I-Cardiology, Aachen, Germany (N.M.); and Medical University of Vienna, Center for Medical Statistics, Informatics and Intelligent Systems, Section for Clinical Biometrics, Vienna, Austria (G.H.). Joachim.Jankowski@charite.de.
authors: Joachim
authors: J
authors: Jankowski
mesh_terms: D000311:Adrenal Glands / Q000737:chemistry*; D000595:Amino Acid Sequence; D000804:Angiotensin II / Q000502:physiology*; D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D053379:Chromogranin A / Q000737:chemistry; D042783:Endothelial Cells / Q000187:drug effects; D006333:Heart Failure / Q000097:blood; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D010455:Peptides / Q000097:blood / Q000737:chemistry / Q000302:isolation & purification* / Q000502:physiology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051381:Rats; D011921:Rats, Inbred WKY; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D044139:Receptor, Angiotensin, Type 2 / Q000819:agonists*; D051436:Renal Insufficiency, Chronic / Q000097:blood; D012084:Renin-Angiotensin System / Q000502:physiology; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014664:Vasodilation / Q000187:drug effects*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D053379:Chromogranin A; D010455:Peptides; D044139:Receptor, Angiotensin, Type 2; C000598983:vasoconstriction-inhibiting factor, human; D000804:Angiotensin II; D048051:p38 Mitogen-Activated Protein Kinases
keywords: AT 2 receptor; angiotensin; angiotensin II; peptides; vasoconstriction