Chronic Administration of Small Nonerythropoietic Peptide Sequence of Erythropoietin Effectively Ameliorates the Progression of Postmyocardial Infarction–Dilated Cardiomyopathy

Abstract

The cardioprotective properties of erythropoietin (EPO) in preclinical studies are well documented, but erythropoietic and prothrombotic properties of EPO preclude its use in chronic heart failure (CHF). We tested the effect of long-term treatment with a small peptide sequence within the EPO molecule, helix B surface peptide (HBSP), that possesses tissue-protective, but not erythropoietic properties of EPO, on mortality and cardiac remodeling in postmyocardial infarction-dilated cardiomyopathy in rats. Starting 2 weeks after permanent left coronary artery ligation, rats received i.p. injections of HBSP (60 mg/kg) or saline two times per week for 10 months. Treatment did not elicit an immune response, and did not affect the hematocrit. Compared with untreated rats, HBSP treatment reduced mortality by 50% (P , 0.05). Repeated echocardiography demonstrated remarkable attenuation of left ventricular dilatation (end-diastolic volume: 41 versus 86%; end-systolic volume: 44 versus 135%; P , 0.05), left ventricle functional deterioration (ejection fraction: 24 versus 263%; P , 0.05), and myocardial infarction (MI) expansion (3 versus 38%; P , 0.05). A hemodynamic assessment at study termination demonstrated normal preload independent stroke work (63 6 5 versus 40 6 4; P , 0.05) and arterioventricular coupling (1.2 6 0.2 versus 2.7 6 0.7; P , 0.05). Histologic analysis revealed reduced apoptosis (P , 0.05) and fibrosis (P , 0.05), increased cardiomyocyte density (P , 0.05), and increased number of cardiomyocytes in myocardium among HBSP-treated rats. The results indicate that HBSP effectively reduces mortality, ameliorates the MI expansion and CHF progression, and preserves systolic reserve in the rat post-MI model. There is also a possibility that HBSP promoted the increase of the myocytes number in the myocardial wall remote from the infarct. Thus, HBSP peptide merits consideration for clinical testing.

Flipping the molecular switch for innate protection and repair of tissues: Long-lasting effects of a non-erythropoietic small peptide engineered from erythropoietin

“…This effect was associated with a significant reduction of necrosis, apoptosis and inflammation measured 24 h after MI induction in the area at risk. In addition, long-term treatment (for 10 months, two times per week) with pHBSP attenuated cardiac remodeling and reduced mortality in a rat model of post-MIdilated cardiomyopathy (Ahmet et al, 2013). Notably, the hematocrit did not change significantly during the 10-month experiment and it did not produce any signs of arterial blood pressure elevation, thus confirming the assertion that continuous administration of pHBSP does not trigger the known undesirable erythropoietic or hemodynamic effects of EPO.…”

Erythropoietin directly stimulates osteoclast precursors and induces bone loss

“…Unrelated to its primary erythropoietic function, EPO-R is expressed in diverse tissues including the brain, reproductive organs, placenta, heart, lungs, intestine, spleen, and bone (8)(9)(10)(11)(12)(13). In line with these findings, new therapeutic indications of EPO were recently suggested for the management of nephropathies, ischemic injuries of several tissues such as intestine, pancreas, and myocardium, neuropathies, liver regeneration, adipose tissue inflammation, and diabetic retinopathy (10,(13)(14)(15)(16)(17)(18)(19)(20)(21)(22). Overall, the ubiquitous expression of EPO-R in nonerythroid cells associated with a plethora of nonhematopoietic functions has recently prompted the experimental evaluation of a vast array of potential future applications of EPO and its derivatives in the clinic.…”

ARA 290, a Nonerythropoietic Peptide Engineered from Erythropoietin, Improves Metabolic Control and Neuropathic Symptoms in Patients with Type 2 Diabetes

“…One promising candidate is ARA 290, which is an 11-amino acid peptide modeled from the three dimensional structure of helix B of the EPO molecule that interacts with the IRR (8). ARA 290 has been evaluated extensively in a wide spectrum of preclinical models, including diet-induced insulin resistance (10), diabetic retinopathy (11), diabetic autonomic neuropathy (12), myocardial infarction (13), chronic heart failure (14), burns (15), traumatic brain injury (16,17) and shock-induced multi-organ failure (18), among others. The results of these studies show that ARA 290 prevents tissue injury, reduces inflammation and activates healing.…”