Novel, selective EPO receptor ligands lacking erythropoietic activityreduce infarct size in acute myocardial infarction in rats

Kiss, Krisztina and Csonka, Csaba and Pálóczi, János and Pipis, Judit and Görbe, Anikó and Kocsis, Gabriella F. and Murlasits, Zsolt and Sárközy, Márta and Szűcs, Gergő and Holmes, Christopher P. and Pan, Yijun and Bhandari, Ashok and Csont, Tamás Bálint and Shamloo, Mehrdad and Woodburn, Kathryn W and Ferdinandy, Péter and Bencsik, Péter (2016) Novel, selective EPO receptor ligands lacking erythropoietic activityreduce infarct size in acute myocardial infarction in rats. PHARMACOLOGICAL RESEARCH, 13 (Pt A). pp. 62-70. ISSN 1043-6618

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Abstract

tErythropoietin (EPO) has been shown to protect the heart against acute myocardial infarction in pre-clinical studies, however, EPO failed to reduce infarct size in clinical trials and showed significant safetyproblems. Here, we investigated cardioprotective effects of two selective non-erythropoietic EPO receptorligand dimeric peptides (AF41676 and AF43136) lacking erythropoietic activity, EPO, and the prolongedhalf-life EPO analogue, darbepoetin in acute myocardial infarction (AMI) in rats. In a pilot study, EPOat 100 U/mL significantly decreased cell death compared to vehicle (33.8 ± 2.3% vs. 40.3 ± 1.5%, p < 0.05)in rat neonatal cardiomyocytes subjected to simulated ischemia/reperfusion. In further studies (studies1–4), in vivo AMI was induced by 30 min coronary occlusion and 120 min reperfusion in male Wis-tar rats. Test compounds and positive controls for model validation (B-type natriuretic peptide, BNP orcyclosporine A, CsA) were administered iv. before the onset of reperfusion. Infarct size (IS) was mea-sured by standard TTC staining. In study 1, 5000 U/kg EPO reduced infarct size significantly compared tovehicle (45.3 ± 4.8% vs. 59.8 ± 4.5%, p < 0.05). In study 2, darbepoetin showed a U-shaped dose-responsecurve with maximal infarct size-reducing effect at 5 �g/kg compared to the vehicle (44.4 ± 5.7% vs.65.9 ± 2.7%, p < 0.01). In study 3, AF41676 showed a U-shaped dose-response curve, where 3 mg/kg wasthe most effective dose compared to the vehicle (24.1 ± 3.9% vs. 44.3 ± 2.5%, p < 0.001). The positive con-trol BNP significantly decreased infarct size in studies 1–3 by approximately 35%. In study 4, AF43136at 10 mg/kg decreased infarct size, similarly to the positive control CsA compared to the appropriatevehicle (39.4 ± 5.9% vs. 58.1 ± 5.4% and 45.9 ± 2.4% vs. 63.8 ± 4.1%, p < 0.05, respectively). This is the firstdemonstration that selective, non-erythropoietic EPO receptor ligand dimeric peptides AF41676 and AF43136 administered before reperfusion are able to reduce infarct size in a rat model of AMI. Therefore,non-erythropoietic EPO receptor peptide ligands may be promising cardioprotective agents.

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