Darbepoetin alpha, a long-acting erythropoeitin derivate, does not alter LPS evoked myocardial depression and gene expression of Bax, Bcl-Xs, Bcl-XL, Bcl-2, and TNF-alpha.
Darbepoetin alpha (DA), a long-acting erythropoietin derivative stimulating erythropoiesis, can, by antiapoptotic effects, mitigate myocardial I/R injury. We tested the hypothesis that DA treatment improves left ventricular function (LV) in LPS evoked cardiomyopathy and alters gene expression of apoptosis-regulating proteins (Bcl-XL, Bcl-2, Bax, and Bcl-Xs) and TNF-alpha. In a prospective, controlled, randomized study in Lewis rats (n = 56; 8 groups), myocardial depression was evoked by LPS administration (serotype O127:B8; 10 mg/kg, i.p.). Darbepoetin alpha or vehicle was injected either 24 h before (pretreatment) or 2 h after LPS injection (treatment). Hearts were isolated 8 h after LPS injection, perfused (Krebs-Henseleit solution) in a Langendorff apparatus, and LV developed pressure and its derivatives were measured. For gene expression analysis, real-time polymerase chain reaction of LV specimen was performed. LPS decreased LV developed pressure (-64.6 +/- 7.9 mmHg) and its derivates by more than 60% in comparison to vehicle (P < 0,01), but this effect was not attenuated by DA pretreatment or DA treatment. LPS administration increased gene expression of Bcl-Xs, Bax, and TNF-alpha, but this was not altered by DA pretreatment. Furthermore, there was no effect on Bcl-Xl and Bcl-2 expression by DA alone. Whereas proapoptotic genes of the myocardium are up-regulated in LPS-induced cardiomyopathy, neither DA pretreatment nor treatment has significant effects on LV function or gene expression. This may suggest cardiac resistance to darbepoetin in LPS-mediated sepsis.
Brendt
Peter
P
Klinik für Anästhesiologie und Intensivmedizin, Universität Duisburg-Essen; and Universitätsklinikum Essen, Essen, Germany. Peter.Brendt@uni-duisburg-essen.de
Frey
Ulrich
U
Adamzik
Michael
M
Schäfer
Simon T
ST
Peters
Jürgen
J
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D009202:Cardiomyopathies / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D000068256:Darbepoetin alfa; D004351:Drug Resistance / Q000187:drug effects; D004921:Erythropoietin / Q000031:analogs & derivatives* / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D006397:Hematinics / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000633:toxicity*; D008297:Male; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis*; D051381:Rats; D011917:Rats, Inbred Lew; D018805:Sepsis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*; D016277:Ventricular Function, Left / Q000187:drug effects; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis*; D051020:bcl-X Protein / Q000096:biosynthesis*
C494828:Bax protein, rat; C494813:Bcl2l1 protein, rat; D006397:Hematinics; D008070:Lipopolysaccharides; D019253:Proto-Oncogene Proteins c-bcl-2; D014409:Tumor Necrosis Factor-alpha; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D004921:Erythropoietin; D000068256:Darbepoetin alfa