Abstract
Strong cardioprotective properties of erythropoietin (EPO) reported over the last 10 years have been difficult to translate to clinical applications for ischemic cardioprotection owing to undesirable parallel activation of erythropoiesis and thrombogenesis. A pyroglutamate helix B surface peptide (pHBP), recently engineered to include only a part of the EPO molecule that does not bind to EPO receptor and thus, is not erythropoietic, retains tissue protective properties of EPO. Here we compared the ability of pHBP and EPO to protect cardiac myocytes from oxidative stress in vitro and cardiac tissue from ischemic damage in vivo. HBP, similar to EPO, increased the reactive oxygen species (ROS) threshold for induction of the mitochondrial permeability transition by 40%. In an experimental model of myocardial infarction induced by permanent ligation of a coronary artery in rats, a single bolus injection of 60 μg/kg of pHBP immediately after coronary ligation, similar to EPO, reduced apoptosis in the myocardial area at risk, examined 24 h later, by 80% and inflammation by 34%. Myocardial infarction (MI) measured 24 h after coronary ligation was similarly reduced by 50% in both pHBP- and EPO-treated rats. Two wks after surgery, left ventricular remodeling (ventricular dilation) and functional decline (fall in ejection fraction) assessed by echocardiography were significantly and similarly attenuated in pHBP- and EPO-treated rats, and MI size was reduced by 25%. The effect was retained during the 6-wk follow-up. A single bolus injection of pHBP immediately after coronary ligation was effective in reduction of MI size in a dose as low as 1 μg/kg, but was ineffective at a 60 μg/kg dose if administered 24 h after MI induction. We conclude that pHBP is equally cardioprotective with EPO and deserves further consideration as a safer alternative to rhEPO in the search for therapeutic options to reduce myocardial damage following blockade of the coronary circulation.
Highlights
Erythropoietin (EPO), a well-known hematopoietic cytokine [1], is used widely clinically for the treatment of anemia [2]
Model by permanent ligation of a coronary artery to the same extent as that of animals that received a single injection of rhEPO [16]
Reduction of myocardial infarction (MI) was transrhEPO [1] or pyroglutamate helix B surface peptide (pHBP) [2] immediately after coronary ligation and animals that received a single injection of pHBP 24 h after coronary ligation [3]
Summary
Erythropoietin (EPO), a well-known hematopoietic cytokine [1], is used widely clinically for the treatment of anemia [2]. EPO has emerged as a potent tissue protective cytokine [3,4]. Translation of significant advances demonstrated in preclinical animal experiments into clinical practice, has been hindered by an understandable caution regarding the classic properties of EPO to stimulate the production of red blood cells and to enhance the risk of thrombosis, an additional cardiovascular risk for already vulnerable patients. These, paradoxically “negative” effects of EPO prompted a search to develop a molecule that retains the tissue-protective properties of EPO, but does not stimulate erythropoiesis. It was established that the tertiary structure of erythropoietin consists of three helices that interact with the erythropoietic receptor, while a fourth region within helix B is believed to interact with a separate receptor to promote tissue protection [9,10,11]. A small peptide (molecular weight 1,257), helix B surface peptide
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