Signal mechanism activated by erythropoietin preconditioning and remote renal preconditioning-induced cardioprotection

Abstract

It has been recently reported that release of erythropoietin could mediate the cardioprotective effects of remote renal preconditioning. However, the mechanism of erythropoietin-mediated cardioprotection in remote preconditioning is still unexplored. Therefore, the present study was designed to investigate the possible signal transduction pathway of erythropoietin-mediated cardioprotection in remote preconditioning in rats. Remote renal preconditioning was performed by four episodes of 5 min renal artery occlusion followed by 5 min reperfusion. Isolated rat hearts were perfused on Langendorff apparatus and were subjected to global ischemia for 30 min followed by 120 min reperfusion. The levels of lactate dehydrogenase (LDH) and creatine kinase (CK) were measured in coronary effluent to assess the degree of myocardial injury. Extent of myocardial infarct size and coronary flow rate was also measured. Remote renal preconditioning and erythropoietin preconditioning (5,000 IUkg(-1), i.p.) attenuated ischemia-reperfusion-induced myocardial injury and produced cardioprotective effects. However, administration of diethyldithiocarbamic acid (150 mg kg(-1) i.p.), a selective NFkB inhibitor, and glibenclamide (5 mg kg(-1) i.p.), a selective K(ATP) channel blocker, attenuated cardioprotective effects of remote preconditioning and erythropoietin preconditioning. However, administration of minoxidil (1 mg kg(-1) i.v.), a selective K(ATP) channel opener, restored the attenuated cardioprotective effects of remote preconditioning and erythropoietin preconditioning in diethyldithiocarbamic acid pretreated rats. These results suggest that K(ATP) channel is a downstream mediator of NFkB activation in remote preconditioning and erythropoietin preconditioning. Therefore, it may be concluded that erythropoietin preconditioning and remote renal preconditioning trigger similar signaling mechanisms for cardioprotection, i.e., NFkB activation followed by opening of K(ATP) channels.

Remote Ischemic Preconditioning and Renoprotection

“…23,24 Other underlying mechanisms may include humoral factors, such as adenosine, bradykinin, erythropoietin, d 1-opioid, and free radicals, released into the systemic circulation, which subsequently protect the remote organ. [25][26][27][28][29] Anti-Inflammatory Pathways Some studies suggested that protective effect of rIPC may be due to the beneficial anti-inflammatory or antioxidant effects, including decreased extracellular levels of noxious metabolites, such as protons and lactate. 25,30 In support of this concept, rIPC reduced neutrophil activation through expression of neutrophil CD11b and platelet neutrophil complexes.…”

Studies on Effect of Stress Preconditioning in Restrain Stress-induced Behavioral Alterations

“…Our own laboratory has documented protective eŠects of ischemic preconditioning in heart 10,11) and brain. 12,13) Moreover, pharmacological preconditioning, 14,15) remote preconditioning, 16,17) and ischemic post-conditioning 18) have been documented to produce tissue-protective eŠects. In the present investigation, stress as an insult was analogous to the ischemic insult and hence, accordingly short episodes of stress were employed before sustained restrain stress, analogous to protocols employed to investigate the protective eŠects of ischemic reconditioning.…”

“…Our own laboratory has documented the protective eŠects of ischemic preconditioning in heart 10,11) and brain. 12,13) This concept has been expanded to include pharmacological preconditioning, 14,15) remote preconditioning, 16,17) and ischemic post-conditioning. 18) The concept of ischemic and pharmacological preconditioning has been extrapolated to investigate the ameliorative role of stress preconditioning on stress-induced pathological changes and there have been reports suggesting the gastroprotective eŠects of stress preconditioning on cold, alcohol, restrain, and water immersion-induced gastric lesions in rats.…”

Clinical Application of Remote Ischemic Preconditioning

“…Theories include the concept that humoral substance(s) such as adenosine or bradykinin are produced by preconditioning, are released into the systemic circulation, and then protect the remote region or organ. 6,13 Other mechanistic factors proposed include erythropoietin, activation of the K ATP channel, 14,15 nitric oxide, 16 delta 1-opioid, 17,18 and free radicals. 17 Another theory is that ischemic preconditioning of 1 region or organ induces a generalized catecholamine stimulation or a sympathomimetic nerve stimulation that then induces cardioprotection.…”