Cardioprotection by a nonerythropoietic, tissue-protective peptide mimicking the 3D structure of erythropoietin

Abstract

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 (≈80%) induced by TNF-α, 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-α, HBSP also inhibited apoptosis (≈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.

The Receptor That Tames the Innate Immune Response

“…After JAK-2 phosphorylation, three dom- inant pathways have been identified. First, similar to erythropoiesis, the STAT pathway (involving STAT3 (heart [69,70]) and STAT5 (brain [71]) are activated, resulting in upregulation of survival signals and subsequent blockade of inflammation-induced apoptosis. Additionally, the STAT pathways activate tissue restorative functions, including neural stem cell differentiation and neurite outgrowth (71).…”

“…Additionally, the STAT pathways activate tissue restorative functions, including neural stem cell differentiation and neurite outgrowth (71). A second major molecular pathway involves phosphatidylinositol 3-kinase (PI3K) and Akt (also known as protein kinase B), which is active in the heart (45,69,70) as well as in the liver and kidney (72). A third pathway also used by the heart, kidney and liver uses mitogen-activated protein kinases (MAPKs) (69,70,72).…”

Reply to Abdelwahid and Smith: The effect on cardiomyocytes of helix B-surface peptide (HBSP), a peptide with cell-protective but not erythropoietic activities of erythropoietin

“…5). We demonstrated that the inhibitory effect of HBSP on cardiomyocyte apoptosis was comparable to that of EPO [figure 1 (2)] and that the signaling pathways of HBSP were the same as those of EPO in cardiomyocytes, except for timing of activation [figure 2 (2)]. These results are reasonable because the downstream signaling pathways activated through the tissue-protective receptor should be the same irrespective of agonist (e.g., EPO or HBSP).…”

“…On the basis of a variety of evidence (4), we believe different EPO receptor isoforms are responsible for these differences. In the study (2), a combination of in vivo and in vitro experiments were performed that confirmed antiapoptotic activity of HBSP in the heart, as well as the activation of molecular signaling pathways associated with antiapoptosis in cardiomyocytes. We agree that there are multiple molecular pathways known (and probably others yet to be identified) that are activated by EPO in myocardial protection, and that these are not redundant (e.g., ref .…”

“…We thank Abdelwahid and Smith (1) for their interest and comments concerning our studies of the cardioprotective effects of a peptide designed to mimic the 3D surface structure of a portion of helix B [helix B-surface peptide (HBSP)] of erythropoietin (EPO) (2). This peptide has been shown to have similar tissue protective and regenerative activities as EPO, but lacks hematopoietic effects (3).…”