Cardioprotection by a nonerythropoietic, tissue-protective peptide mimicking the 3D structure of erythropoietin.
Erythropoietin (EPO), originally identified for its critical hormonal role in regulating production and survival of erythrocytes, is a member of the type 1 cytokine superfamily. Recent studies have shown that EPO has cytoprotective effects in a wide variety of tissues, including the heart, by preventing apoptosis. However, EPO also has undesirable effects, such as thrombogenesis. In the present study, we investigated whether a helix B-surface peptide (HBSP), a nonerythropoietic, tissue-protective peptide mimicking the 3D structure of erythropoietin, protects cardiomyocytes from apoptosis in vitro and in vivo. In cultured neonatal rat cardiomyocytes, HBSP clearly inhibited apoptosis (approximately 80%) induced by TNF-alpha, which was comparable with the effect of EPO, and activated critical signaling pathways of cell survival, including Akt, ERK1/2, and STAT3. Among these pathways, Akt was shown to play an essential role in HBSP-induced prevention of apoptosis, as assessed by using a small interfering RNA approach. In the dilated cardiomyopathic hamster (J2N-k), whose cardiac tissues diffusely expressed TNF-alpha, HBSP also inhibited apoptosis (approximately 70%) and activated Akt in cardiomyocytes. Furthermore, the levels of serum creatine kinase activity and of cardiac expression of atrial natriuretic peptide, a marker of chronic heart failure, were down-regulated in animals treated with HBSP. These data demonstrate that HBSP protects cardiomyocytes from apoptosis and leads to a favorable outcome in failing hearts through an Akt-dependent pathway. Because HBSP does not have the undesirable effects of EPO, it could be a promising alternative for EPO to treat cardiovascular diseases, such as myocardial infarction and heart failure.
Ueba
Hiroto
H
Department of Integrated Medicine 1, Saitama Medical Center, Jichi Medical University, Saitama City 330-8503, Japan.
Brines
Michael
M
Yamin
Michael
M
Umemoto
Tomio
T
Ako
Junya
J
Momomura
Shin-ichi
S
Cerami
Anthony
A
Kawakami
Masanobu
M
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002316:Cardiotonic Agents / Q000737:chemistry* / Q000494:pharmacology; D004921:Erythropoietin / Q000737:chemistry* / Q000627:therapeutic use; D018716:Molecular Mimicry; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D011487:Protein Conformation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats
D002316:Cardiotonic Agents; D010455:Peptides; D004921:Erythropoietin; D051057:Proto-Oncogene Proteins c-akt