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Erythropoietin requires endothelial nitric oxide synthase to counteract tnf-α-induced microcirculatory dysfunction in murine striated muscle


Contaldo, C; Lindenblatt, N; Elsherbiny, A; Högger, D C; Borozadi, M K; Vetter, S T; Lang, K S; Handschin, A E; Giovanoli, P (2010). Erythropoietin requires endothelial nitric oxide synthase to counteract tnf-α-induced microcirculatory dysfunction in murine striated muscle. Shock, 35(3):315-321.

Abstract

In the present study we aimed to evaluate whether erythropoietin (EPO) treatment may exert non-hematopoietic endothelial protection against tumor necrosis factor alpha (TNF-α) induced microvascular inflammation and to determine the involvement of the nitric oxide (NO)-producing enzyme isoforms endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS). Murine dorsal skinfold chambers of wild type (wt) animals were topically stimulated with TNF-α after pre-treatment with epoietin beta (1,000 IU/kg body weight (BW), intraperitoneally (i.p.)) or physiological saline. Leukocyte behavior, microvascular perfusion and apoptosis were assessed by in vivo fluorescence microscopy. To study the involvement of NO, we compared eNOS deficient (eNOS-/-) and iNOS deficient (iNOS-/-) mice to wt animals. TNF-α associated leukocyte activation, perfusion failure, and apoptosis were substantially attenuated in EPO pre-treated wt mice, which was accompanied by marked reduction of perivascular infiltration with F4/80 stained macrophages. The anti-inflammatory protective effects of EPO were abolished in eNOS-/-, but not in iNOS-/- mice, both with unaffected intercellular adhesion molecule 1 (ICAM-1) expression. However, the anti-apoptotic effect of EPO was maintained in both eNOS-/- and iNOS-/- mice, indicating that this mechanism might rather be independent of NO. We conclude that EPO treatment elicits protection against TNF-α induced microcirculatory dysfunction, depending on NO derived from endothelial cells, but not on the inducible isoform.

Abstract

In the present study we aimed to evaluate whether erythropoietin (EPO) treatment may exert non-hematopoietic endothelial protection against tumor necrosis factor alpha (TNF-α) induced microvascular inflammation and to determine the involvement of the nitric oxide (NO)-producing enzyme isoforms endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS). Murine dorsal skinfold chambers of wild type (wt) animals were topically stimulated with TNF-α after pre-treatment with epoietin beta (1,000 IU/kg body weight (BW), intraperitoneally (i.p.)) or physiological saline. Leukocyte behavior, microvascular perfusion and apoptosis were assessed by in vivo fluorescence microscopy. To study the involvement of NO, we compared eNOS deficient (eNOS-/-) and iNOS deficient (iNOS-/-) mice to wt animals. TNF-α associated leukocyte activation, perfusion failure, and apoptosis were substantially attenuated in EPO pre-treated wt mice, which was accompanied by marked reduction of perivascular infiltration with F4/80 stained macrophages. The anti-inflammatory protective effects of EPO were abolished in eNOS-/-, but not in iNOS-/- mice, both with unaffected intercellular adhesion molecule 1 (ICAM-1) expression. However, the anti-apoptotic effect of EPO was maintained in both eNOS-/- and iNOS-/- mice, indicating that this mechanism might rather be independent of NO. We conclude that EPO treatment elicits protection against TNF-α induced microcirculatory dysfunction, depending on NO derived from endothelial cells, but not on the inducible isoform.

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Additional indexing

Other titles:Epo requires enos to counteract tnf-α induced microcirculatory dysfunction in murine striated muscle
Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Division of Surgical Research
04 Faculty of Medicine > University Hospital Zurich > Clinic for Reconstructive Surgery
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:12 January 2010
Deposited On:17 Feb 2011 14:03
Last Modified:07 Dec 2017 07:20
Publisher:Lippincott Wiliams & Wilkins
ISSN:1073-2322
Publisher DOI:https://doi.org/10.1097/SHK.0b013e3181fd0700
PubMed ID:20926979

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