Acute cardioprotective effects of erythropoietin in infant rabbits are mediated by activation of protein kinases and potassium channels

Abstract

Erythropoietin is protective against cardiac ischemia, but the underlying mechanisms are unknown. We determined whether erythropoietin (0.5 - 10.0 U/ml) confers acute cardioprotection in infant rabbit hearts and the contribution of protein kinases, nitric oxide synthase and potassium channels to the underlying mechanism. Hearts from normoxic infant New Zealand White rabbits (n=8/group) were isolated and perfused in the Langendorff mode. Biventricular function was recorded under steady-state conditions prior to 30 min global no-flow ischemia and 35 min reperfusion. Administration of erythropoietin for 15 min immediately prior to ischemia resulted in a concentration-dependent increase in recovery of left and right ventricular developed pressure in rabbit hearts following myocardial ischemia and reperfusion. The optimal concentration of erythropoietin that afforded maximum recovery of developed pressure was manifest at 1.0 U/ml. Erythropoietin (1.0 U/ml) treatment resulted in phosphorylation of PKC, p38 MAP kinase and p42/44 MAP kinase. The cardioprotective effects of erythropoietin were abolished by the protein kinase inhibitors SB203580 (p38 MAP kinase), PD98059 (p42/44 MAP kinase) and chelerythrine (PKC) as well as the potassium channel blockers glibenclamide, HMR 1098, 5-HD and Paxilline. Nitrite and nitrate release from hearts before (2.3 +/- 0.9 nmol/min/g) and after (2.4 +/- 1.9 nmol/min/g) 15 min treatment with erythropoietin (1.0 U/ml) were not different. L-NAME and L-NMA did not block the cardioprotective effect of erythropoietin. We conclude the rapid activation of potassium channels and protein kinases by erythropoietin represents an important new mechanism for increasing cardioprotection.

Erythropoietin affords additional cardioprotection to preconditioned hearts by enhanced phosphorylation of glycogen synthase kinase-3β

“…However, recent studies have shown that EPO has potent cell-protective effects in various tissues, including myocardium, in addition to its effect on erythropoiesis (5-7, 12, 16, 25, 26, 33-35, 43). The presence of the EPO receptor in cardiomyocytes has been indicated in RT-PCR and immunoblot experiments (40), and administration of EPO before or at the time of ischemia has been shown to reduce necrosis, apoptosis, and ventricular dysfunction after ischemia-reperfusion (6,7,12,16,25,(33)(34)(35)43). These features of EPO-induced cardioprotection are similar to those of ischemic preconditioning (PC).…”

Cyclooxygenase-2 plays an essential part in cardioprotection of delayed phase of recombinant human erythropoietin preconditioning in rats

“…20 Parsa et al 12 showed the most significant protection was noted when rhEPO was given 12 hours before I-R than given at the onset of ischaemia or reperfusion in rabbits. The molecular signals by which rhEPO provides its benefit against cardiac iscahemic injury are currently unclear, and just a few key steps and signal pathways have been unveiled, for example, PKCe and MAPKs in the acute EPC, 9 and JAK-STAT pathway in the delayed one. 12 Both the acute or delayed protection of EPC might be the result of a complex cascade of cellular events, therefore, currently it is hard to tell the similarity or difference between them.…”

“…[3][4][5][6] Varieties of preconditioning (PC) stimuli (for example, ischaemic preconditioning (IPC) and some forms of PPC) are capable of eliciting potent cardioprotection against I-R by activating common mediators and signal transduction pathways. 7 8 Activation of ATP sensitive K + (K ATP ) channels, 9 protein kinase Ce (PKCe), 10 mitogen activated protein kinase (MAPKs), 9 10 and Janus tyrosine kinase (JAK) signal transducers and activators of transcription (STAT), [10][11][12] which are shown to play critical parts in IPC have also been identified important and necessary in the protection of rhEPO preconditioning (EPC).…”

Erythropoietin in Patients With Acute ST-Segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention

“…The study drug was given at 3 distinct time points: immediately after successful PCI in the catheterization laboratory and at 24 hours and 48 hours after random assignment. Each time, patients received either 3.33ϫ10 4 IU of recombinant human epoetin-␤ (NeoRecormon; F. Hoffmann-La Roche, Basel, Switzerland) or a matching placebo intravenously for 30 minutes. Postinterventional antithrombotic therapy consisted of clopidogrel 75 mg twice a day for 3 days followed by 75 mg/d for at least 6 months.…”

“…2 Numerous ex vivo and in vivo studies have shown a protective role of human recombinant erythropoietin during ischemic and reperfusion in the heart with a reduction in infarct size and apoptosis. [3][4][5][6] Erythropoietin prevented not only apoptosis of endothelial cells but also of cardiomyocytes by activating the PI3K/Akt pathway. 7 Moreover, activation of mitogen-activated kinase (MAPK) p38, p42/44, protein kinase C, and potassium channels mediates the protective effects of erythropoietin.…”