Identification of the Vasoconstriction-Inhibiting Factor (VIF), a Potent Endogenous Cofactor of Angiotensin II Acting on the Angiotensin II Type 2 Receptor

Silvia Salem; Vera Jankowski; Yaw Asare; Elisa Liehn; Pia Welker; Ana Raya-Bermudez; Carmen Pineda-Martos; Mariano Rodriguez; Juan Rafael Muñoz-Castañeda; Heike Bruck; Nikolaus Marx; Fernanda B Machado; Mareike Staudt; Georg Heinze; Walter Zidek; Joachim Jankowski

doi:10.1161/CIRCULATIONAHA.114.013168

Identification of the Vasoconstriction-Inhibiting Factor (VIF), a Potent Endogenous Cofactor of Angiotensin II Acting on the Angiotensin II Type 2 Receptor

Circulation. 2015 Apr 21;131(16):1426-34. doi: 10.1161/CIRCULATIONAHA.114.013168. Epub 2015 Mar 25.

Authors

Silvia Salem¹, Vera Jankowski¹, Yaw Asare¹, Elisa Liehn¹, Pia Welker¹, Ana Raya-Bermudez¹, Carmen Pineda-Martos¹, Mariano Rodriguez¹, Juan Rafael Muñoz-Castañeda¹, Heike Bruck¹, Nikolaus Marx¹, Fernanda B Machado¹, Mareike Staudt¹, Georg Heinze¹, Walter Zidek¹, Joachim Jankowski²

Affiliations

¹ 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.).
² 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.). [email protected].

PMID: 25810338
DOI: 10.1161/CIRCULATIONAHA.114.013168

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.

Methods and 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.

Keywords: AT 2 receptor; angiotensin; angiotensin II; peptides; vasoconstriction.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adrenal Glands / chemistry*
Amino Acid Sequence
Angiotensin II / physiology*
Animals
Cattle
Cells, Cultured
Chromogranin A / chemistry
Endothelial Cells / drug effects
Heart Failure / blood
Humans
MAP Kinase Signaling System / drug effects
Male
Mice
Molecular Sequence Data
Peptides / blood
Peptides / chemistry
Peptides / isolation & purification*
Peptides / physiology
Protein Processing, Post-Translational / drug effects
Rats
Rats, Inbred WKY
Rats, Sprague-Dawley
Rats, Wistar
Receptor, Angiotensin, Type 2 / agonists*
Renal Insufficiency, Chronic / blood
Renin-Angiotensin System / physiology
Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
Vasodilation / drug effects*
p38 Mitogen-Activated Protein Kinases / metabolism

Substances

Chromogranin A
Peptides
Receptor, Angiotensin, Type 2
vasoconstriction-inhibiting factor, human
Angiotensin II
p38 Mitogen-Activated Protein Kinases