Institutional members access full text with Ovid®

Share this article on:

Erythropoietin-induced hypertension and vascular injury in mice overexpressing human endothelin-1: exercise attenuated hypertension, oxidative stress, inflammation and immune response

Barhoumi, Tlilia,d; Briet, Mariea,b,e; Kasal, Daniel A.a,c; Fraulob-Aquino, Julio Cesara; Idris-Khodja, Nourredinea; Laurant, Pascald; Paradis, Pierrea; Schiffrin, Ernesto L.a,b

doi: 10.1097/HJH.0000000000000101
ORIGINAL PAPERS: Pathophysiological aspects

Objective: Erythropoietin used to correct anaemia in chronic kidney disease (CKD) has been shown to increase blood pressure (BP) in CKD patients and experimental animals. Endothelin (ET)-1 expression is increased in CKD animals and patients, and enhanced by erythropoietin. Erythropoietin-induced BP rise was blunted by ETA receptor blockers. This study was designed to determine whether preexisting endothelin (ET)-1 overexpression is required for erythropoietin to cause adverse vascular effects and whether this could be prevented by exercise training.

Methods: Eight to 10-week old male wild-type mice and mice with endothelial-specific ET-1 overexpression (eET-1) were treated or not with EPO (100 IU/kg, SC, 3 times/week). eET-1 was subjected or not to swimming exercise training (1 h/day, 6 days/week) for 8 weeks. SBP, mesenteric artery endothelial function and remodelling, NADPH oxidase activity, reactive oxygen species (ROS) generation, vascular cell adhesion protein (VCAM)-1, monocyte/macrophage infiltration, T regulatory cells (Tregs) and tissue ET-1 and plasma endothelin were determined.

Results: Erythropoietin increased SBP by 24 mmHg (P < 0.05) and decreased by 25% vasodilatory responses to acetylcholine (P < 0.01) in eET-1 mice. Erythropoietin enhanced ET-1 induced increase in resistance artery media/lumen ratio (31%, P < 0.05), aortic NADPH oxidase activity (50%, P < 0.05), ROS generation (93%, P < 0.001), VCAM-1 (80%, P < 0.01) and monocyte/macrophage infiltration (159%, P < 0.001), and raised plasma and aortic ET-1 levels (≥130%, P < 0.05). EPO had no effect in wild-type mice. Exercise training prevented all of the above (P < 0.05).

Conclusion: Erythropoietin-induced adverse vascular effects are dependent on preexisting elevated ET-1 expression. Exercise training prevented erythropoietin-induced adverse vascular effects in part by inhibiting ET-1 overexpression-induced oxidative stress, inflammation and immune activation.

aLady Davis Institute for Medical Research

bDepartment of Medicine, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, Quebec, Canada

cState University of Rio de Janeiro, Rio de Janeiro, Brazil

dUniversité d’Avignon et des Pays de Vaucluse-Avignon, Avignon

eDepartment of Pharmacology and Institut National de la Santé et de la Recherche Médicale U970-PARCC, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France

Correspondence to Ernesto L. Schiffrin, CM, MD, PhD, FRSC, FRCPC, Department of Medicine, Sir Mortimer B. Davis-Jewish General Hospital, #B-127, 3755 Cote Ste-Catherine Road, Montreal, QC H3T 1E2, Canada. Tel: +1 514 340 7538; fax: +1 514 340 7539; e-mail: ernesto.schiffrin@mcgill.ca

Abbreviations: ACh, acetylcholine; BP, blood pressure; CKD, chronic kidney disease; DAPI, 4’,6-diamidino-2-phenylindole; DHE, dihydroethidium; eET-1, mice with endothelium-specific endothelin-1 overexpression; EPO, erythropoietin; ET, endothelin; ETAR, endothelin type A receptor; FOXP3, forkhead box P3; L-NAME, Nω-nitro-L-arginine methyl ester; PBST, phosphate buffered saline containing 0.1% Tween-20; RAB, reactive oxygen species assay buffer; ROS, reactive oxygen species; Treg, T regulatory lymphocytes; VCAM-1, vascular cell adhesion protein 1

Received 13 May, 2012

Accepted 4 December, 2013

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (http://www.jhypertension.com).

© 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins