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Calcitonin gene-related peptide, heme oxygenase-1, endothelial progenitor cells and nitric oxide-dependent vasodilation relationships in a human model of angiotensin II type-1 receptor antagonism

Calò, Lorenzo A.a; Davis, Paul A.b; Pagnin, Elisaa; Dal Maso, Luciaa; Caielli, Paolaa; Rossi, Gian P.a

doi: 10.1097/HJH.0b013e32835414f7

Objective: An increased number of endothelial progenitor cells (EPCs), which correlated with heme oxygenase-1 gene expression and nitric oxide-mediated vasodilation [flow-mediated dilation (FMD)], has been recently reported by us in Bartter/Gitelman syndromes, rare diseases that represent a human model of endogenous angiotensin (Ang) II type-1 receptor antagonism and depicting an opposite picture of hypertension. Calcitonin gene-related peptide (CGRP), which prevents circulating EPCs senescence and reverses Ang II-induced EPCs senescence is reduced in hypertensive patients, its level is stimulated by heme oxygenase-1 and is related with stimulation of nitric oxide. This study reports on CGRP concentration and heme oxygenase-1 protein level in Bartter/Gitelman syndrome's patients compared with healthy individuals and analyzes their relationships with EPCs [CD34+kinase insert domain receptor (KDR+), CD133+KDR+, CD34+CD133+KDR+) as well as FMD.

Methods and results: CGRP concentration (ELISA) and heme oxygenase-1 protein level (sandwich immunoassay) were higher in Bartter/Gitelman syndrome : 38.20 ± 8.23 pg/ml vs. 25.07 ± 3.51, P < 0.002 and 9.44 ± 3.1 ng/ml vs. 5.52 ± 1.1, P < 0.007, respectively. CD133+KDR+ and CD34+CD133+KDR+ (direct three-color flow cytometry analysis) and FMD (B-mode echo scan of brachial artery) were confirmed higher in Bartter/Gitelman syndrome. CGRP and heme oxygenase-1 strongly correlated (P < 0.0001) and did not differ by group. In Bartter/Gitelman syndrome, both CGRP and heme oxygenase-1 were strongly correlated with both EPCs and FMD.

Conclusions: Using a human model opposite to hypertension, this study provides information on the relationships between CGRP, heme oxygenase-1, FMD, major clinical and biochemical factors involved in cardiovascular disease, and EPC-specific populations and may also serve to confirm the utility of Bartter/Gitelman syndrome patients in delineating EPCs and related factors roles in the pathophysiology of cardiovascular remodeling in humans.

aDepartment of Medicine, Clinica Medica 4, University of Padova, Padova, Veneto, Italy

bDepartment of Nutrition, University of California, Davis, Yolo, California, USA

Correspondence to Lorenzo A. Calò MD, PhD, Department of Medicine, Clinica Medica 4, University of Padova, Via Giustiniani 2, 35128 Padova, Veneto, Italy. Tel: +39 049 8218701 8212279; fax: +39 049 8754179; e-mail:

Abbreviations: Ang II, angiotensin II; AT1R, Ang II type-1 receptor; BP, blood pressure; CGRP, calcitonin gene-related peptide; EPCs, endothelial progenitor cells; FMD, NO-dependent vasodilation; KDR+, kinase insert domain receptor; mAbs, monoclonal antibodies; RGS, G-protein signaling

Received 28 December, 2011

Revised 13 February, 2012

Accepted 22 March, 2012

© 2012 Lippincott Williams & Wilkins, Inc.