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


CONCLUSIONS
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.
Tlili
T
Barhoumi
Marie
M
Briet
Daniel A
DA
Kasal
Julio Cesar
JC
Fraulob-Aquino
Nourredine
N
Idris-Khodja
Pascal
P
Laurant
Pierre
P
Paradis
Ernesto L
EL
Schiffrin
D000818:Animals; D001794:Blood Pressure; D019332:Endothelin-1 / Q000097:blood*; D004921:Erythropoietin / Q000097:blood*; D006400:Hematocrit; D006801:Humans; D006973:Hypertension / Q000503:physiopathology*; D007107:Immune System; D007249:Inflammation; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D019255:NADPH Oxidases / Q000378:metabolism; D018384:Oxidative Stress; D010805:Physical Conditioning, Animal; D017382:Reactive Oxygen Species; D013550:Swimming; D013599:Systole
D019332:Endothelin-1; D017382:Reactive Oxygen Species; D004921:Erythropoietin; D019255:NADPH Oxidases