Cardioprotection of exogenous erythropoietin in mice with ligature-induced aortic stenosis: effects on maladaptive cardiac hypertrophy.
Pre-operative treatment with recombinant human erythropoietin may improve aortic stenosis patients' condition, including anemia and/or cardiac dysfunction, for subjecting to aortic valve replacement. In this study, we tested this hypothesis in a mouse model of aortic stenosis. Adult male mice were subjected to either aortic stenosis created by aortic ligature or sham operation. Aortic stenosis for 4 weeks caused cardiac hypertrophy, pulmonary congestion and left ventricular dysfunction. It was associated with increased levels of tumor necrosis factor-alpha in serum and myocardium, and reduced levels of interleukin-10 in myocardium but not in serum. Myocyte apoptosis rate, level of cleaved caspase 3, activity of nuclear factor-kappaB and expression of p38-MAPK pathway were also elevated. Erythropoietin treatment increased hematocrit but did not prevent the development of cardiac hypertrophy. It, however, reduced the apoptosis, prevented the increases in tumor necrosis factor-alpha, nuclear factor-kappaB activation and phosphorylation of p38, and attenuated the increases in lung weight, the decreases in LVEF and LVFS, and the increases in LVDd and LVDs. In conclusion recombinant human erythropoietin has cardioprotective effects in maladaptive cardiac hypertrophy by inhibiting nuclear factor-kappaB activation, phosphorylation of p38-MAPK pathway, and production of tumor necrosis factor-alpha, together leading to a reduced apoptosis.
Zheng
L
L
Department of Thoracic and Cardiovascular Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Xu
J
J
Qiu
W
W
Liu
X
X
Zhao
C-M
CM
Chen
D
D
Chen
Y
Y
D000818:Animals; D001024:Aortic Valve Stenosis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D017209:Apoptosis / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000502:physiology; D006332:Cardiomegaly / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002316:Cardiotonic Agents / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004921:Erythropoietin / Q000008:administration & dosage / Q000627:therapeutic use*; D008026:Ligation; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation; D011994:Recombinant Proteins / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology
D051017:Apoptosis Regulatory Proteins; D002316:Cardiotonic Agents; D016328:NF-kappa B; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D004921:Erythropoietin; D048051:p38 Mitogen-Activated Protein Kinases