Darbepoetin alfa exerts a cardioprotective effect in autoimmune cardiomyopathy via reduction of ER stress and activation of the PI3K/Akt and STAT3 pathways.
Dilated human cardiomyopathy is associated with suppression of the prosurvival phosphatidylinositol-3-kinase (PI3K)/Akt and STAT3 pathways. The present study was carried out to determine if restoration of the PI3K/Akt and STAT3 activity by darbepoetin alfa improved cardiac function or reduced cardiomyocyte apoptosis in rabbit autoimmune cardiomyopathy induced by a peptide corresponding to the second extracellular loop of the ss(1)-adrenergic receptor (ss(1)-EC(II)). We found that ss(1)-EC(II) immunization produced progressive LV dilation, systolic dysfunction and myocyte apoptosis as measured by TUNEL, single-stranded DNA antibody, and active caspase-3. These changes were associated with activation of p38 mitogen-activated protein kinase (MAPK), endoplasmic reticulum stress markers (GRP78 and CHOP), and increased cleavage of procaspase-12, as well as decreased phosphorylation of Akt and STAT3, and decreased Bcl2/Bax ratio. As expected, darbepoetin alfa treatment increased phosphorylation of Akt and STAT3. It also increased the myocardial expression of erythropoietin receptor which was reduced in the failing myocardium, and improved cardiac function in the ss(1)-EC(II)-immunized animals. The latter was associated with reductions of myocyte apoptosis and cleaved caspase-3, as well as reversal of increased phosphorylation of p38-MAPK, increased ER stress, and decline in Bcl2/Bax ratio. The anti-apoptotic effects of darbepoetin alfa via Akt and STAT activation were also demonstrated in cultured cardiomyocytes treated with the anti-ss(1)-EC(II) antibody. These effects of darbepoetin alfa in vitro were prevented by LY294002 and STAT3 peptide inhibitor. Thus, we conclude that darbepoetin alfa improves cardiac function and prevents progression of dilated cardiomyopathy probably by activating the PI3K/Akt and STAT3 pathways and reducing ER stress.
Mao
Weike
W
Cardiology Division, Department of Medicine, University of Rochester Medical Center, Rochester, New York 14642, USA.
Iwai
Chikao
C
Liu
Jiahao
J
Sheu
Shey-Shing
SS
Fu
Michael
M
Liang
Chang-Seng
CS
D000818:Animals; D000831:Animals, Newborn; D001327:Autoimmune Diseases / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D002311:Cardiomyopathy, Dilated / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D002316:Cardiotonic Agents / Q000627:therapeutic use; D002478:Cells, Cultured; D000068256:Darbepoetin alfa; D004721:Endoplasmic Reticulum / Q000187:drug effects*; D000091342:Endoplasmic Reticulum Chaperone BiP; D004921:Erythropoietin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006801:Humans; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000276:immunology; D018384:Oxidative Stress / Q000187:drug effects*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology
D002316:Cardiotonic Agents; D000068256:Darbepoetin alfa; D000091342:Endoplasmic Reticulum Chaperone BiP; D004921:Erythropoietin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D050796:STAT3 Transcription Factor; C000717247:HSPA5 protein, human