Abstract 264: Erythropoietin-induced Hypertension and Vascular Injury in Mice Overexpressing Human Endothelin-1 Was Attenuated by Exercise
Background: Erythropoietin (EPO) is used to correct anemia in chronic kidney disease (CKD). EPO has been shown to increase blood pressure (BP) in patients and animals with CKD. This BP rise can be blunted by endothelin (ET) A receptor blockers. Chronic exercise prevents or reduces development of cardiovascular disease. However, it is unknown whether exercise prevents EPO-induced hypertension. We hypothesized that EPO treatment would exacerbate endothelin (ET)-1-induced vascular damage and increase BP, and that exercise training might prevent these effects.
Methods: Eight to 10-week old male mice overexpressing human preproET-1 in the endothelium (eET-1) were treated with EPO (100 U/kg, s.c, 3 times/week) or not, and subjected to swimming exercise (1 h/d, 5 d/week) for 8 weeks or maintained in sedentary condition (n=7-8). Wild-type (WT) mice were also treated or not with EPO. Systolic BP (SBP) was measured by the tail-cuff method. Endothelial function was assessed in mesenteric arteries by pressurized myography. NADPH oxidase activity was assessed in aorta or renal cortex of by lucigenin chemiluminescence, reactive oxygen species (ROS) by dihydroethidium staining, and monocyte/macrophage and T regulatory cell (FoxP3) infiltration, and VCAM-1 by immunofluorescence staining.
Results: EPO increased SBP by 24 mmHg (P<0.05) and impaired vasodilatory responses to acetylcholine in eET-1 (68% vs. 91%, P<0.01). NADPH oxidase activity was 2-fold higher in eET-1 than in WT (P<0.05), and further increased 1.5-fold by EPO (P<0.01). ROS production in aorta of WT was enhanced 2-fold (P<0.01) by EPO, which increased ROS in eET-1 a further 9-fold (P<0.01). EPO increased monocyte/macrophage infiltration in aorta of WT 2.5-fold (P<0.01), and in eET-1 a further 2.7-fold (P<0.05). VCAM-1 expression in aorta was 2.7-fold higher in eET-1 than in WT (P<0.05). All of the above was prevented by exercise (P<0.05). Exercise with or without EPO increased T regulatory FoxP3+ lymphocytes in renal cortex 3-fold compared to eET-1 and WT (P<0.01).
Conclusions: Exercise prevents EPO-induced BP elevation and vascular damage through a mechanism involving decreased vascular oxidative stress and inflammation.
- © 2012 by American Heart Association, Inc.