Alteration in Erythropoietin-Induced Cardioprotective Signaling by Postinfarct Ventricular Remodeling

Abstract

Postinfarct remodeling impairs mechanisms of ischemic preconditioning. We examined whether myocardial response to activation of the erythropoietin (EPO) receptor is modified by postinfarct remodeling. Four weeks after induction of myocardial infarction (MI) by coronary ligation in post-MI group (post-MI) or a sham operation in sham group (sham), rat hearts were isolated and subjected to 25-min global ischemia/2-h reperfusion. Infarct size was expressed as a percentage of risk area (i.e., left ventricle) from which scarred infarct was excluded (%I/R). The heart weight was 15% larger in post-MI, but there was no intergroup difference in plasma EPO levels or myocardial EPO receptor levels. EPO infusion (5 U/ml) significantly reduced %I/R from 59.9 Ϯ 4.1 to 36.2 Ϯ 4.2 in sham and from 58.1 Ϯ 5.0 to 35.2 Ϯ 4.0 in post-MI. This EPO-induced protection was sensitive to a phosphatidylinositol 3-kinase (PI3K) inhibitor, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002), in sham. However, neither LY294002 nor wortmannin inhibited the EPO-induced protection in post-MI. Phosphorylation of Janus kinase 2 by EPO was attenuated and phosphorylation of Akt was not detected in post-MI. A guanylyl cyclase inhibitor, 1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one, and a mitochondrial ATP-sensitive K ϩ channel (mitoK ATP channel) blocker, 5-hydroxydecanoate, inhibited EPO-induced protection in both sham and post-MI. Suppressor of cytokine signaling (SOCS)-1 protein level was higher by 50% in post-MI than in sham, although SOCS-3 levels were similar. These findings suggest that postinfarct remodeling disrupts cellular signaling from the EPO receptor to PI3K, presumably by increased SOCS-1. However, in the remodeled myocardium, lack of PI3K/Akt activation by the EPO receptor seems to be compensated by a mechanism upstream of the guanylyl cyclasemitoK ATP channel pathway to achieve EPO-induced protection.Erythropoietin (EPO) is an erythropoietic hormone that is produced primarily in juxtatubular cells of the kidney in response to hypoxia, and administration of recombinant human EPO has been used as a standard therapy for renal anemia for a decade. Recently, broad cytoprotective effects of EPO in various tissues have received attention (Maiese et al., 2005). In studies using rat and rabbit hearts, recombinant human EPO as well as derivatives of EPO administered before or at the time of ischemia suppressed myocardial necrosis and apoptosis, ventricular dysfunction, and ventricular remodeling after ischemia/reperfusion (IR) (Calvillo et al., 2003;Moon et al., 2003;Parsa et al., 2003;Lipsic et al., 2004;Wright et al., 2004;Fiordaliso et al., 2005). Furthermore, these studies consistently showed that the phosphatidylinositol 3-kinase (PI3K)-Akt pathway plays a crucial role in the EPO-induced cardioprotection (Parsa et al., 2003;Cai and Semenza, 2004;Bullard et al., 2005;Hanlon et al., 2005;Rafiee et al., 2005), although involvement of mitogen-activated protein kinase, protein kinase C (PKC), and mitochondrial ATP-sensitive K ϩ...

Sitagliptin decreases ventricular arrhythmias by attenuated glucose-dependent insulinotropic polypeptide (GIP)-dependent resistin signalling in infarcted rats

“…The drugs were perfused for 60 min. The doses of WM [27] and resistin [27] used in that study have been used previously. All of the hearts (n = 5 each group) were used for western blot analysis for NGF at the remote zone.…”

Erythropoietin and Oxidative Stress

“…Phosphorylation of Akt in conjunction with EPO administration leads to its activation and protects against genomic DNA degradation and membrane PS exposure . Up-regulation of Akt activity during multiple injury paradigms, such as vascular and cardiomyocyte ischemia (Miki, et al, 2006, Parsa, et al, 2003, free radical exposure , Matsuzaki, et al, 1999, matrix detachment (Rytomaa, et al, 2000), neuronal axotomy (Namikawa, et al, 2000), N-methyl-D-aspartate toxicity (Dzietko, et al, 2004), hypoxia (Chong, et al, 2002b, β-amyloid toxicity (Chong, et al, 2005d, Martin, et al, 2001, DNA damage , Chong, et al, 2002b, Henry, et al, 2001, metabotropic ligand (Anjaneyulu, et al, 2008 and receptor signaling , cell metabolic pathways (Chong, et al, 2005g, Maiese and, and oxidative stress increases cell survival. Akt also can directly control microglial activation through the prevention of Bcl-x L degradation and the inhibition of caspase 1-, 3-, and 9-like activities .…”

“…Activation of Akt is usually cytoprotective, such as during free radical exposure , Matsuzaki, et al, 1999, hyperglycemia (Anitha, et al, 2006), endothelial cell hypoxia (Chong, et al, 2002b), β-amyloid toxicity , Chong, et al, 2005d, cardiomyopathy (Kim, et al, 2008), and oxidative stress . EPO uses the PI 3-K/Akt pathway in a variety of experimental models of injury (Bahlmann, et al, 2004, Chong, et al, 2002b, Chong, et al, 2003e, Chong and Maiese, 2007a, Miki, et al, 2006, Parsa, et al, 2003, Sharples, et al, 2004, Um, et al, 2007, Um and Lodish, 2006, Wu, et al, 2007b. These can involve transcription factor regulation (Chong and Maiese, 2007a), maintenance of ΔΨ m , prevention of cytochrome c release , and blockade of caspase activity , Chong, et al, 2002b.…”

Triple play: Promoting neurovascular longevity with nicotinamide, WNT, and erythropoietin in diabetes mellitus

“…Through the Wnt pathway, EPO may offer an attractive therapy to maintain proper cellular metabolism and mitochondrial membrane potential (ΔΨ m ) during conditions of oxidative stress and DM. In cell culture and animal studies, EPO is cytoprotective during elevated glucose [150] and has the capacity to prevent the depolarization of the mitochondrial membrane that also affects the release of cytochrome c [105,106,110]. With the Wnt pathway, EPO maintains the expression of Wnt1 during elevated glucose exposure and prevents loss of Wnt1 expression that would normally occur in the absence of EPO during elevated glucose.…”

“…Phosphorylation of Akt leads to its activation and protects cells against genomic DNA degradation and membrane PS exposure [45,61,105]. Up-regulation of Akt activity during multiple injury paradigms, such as vascular and cardiomyocyte ischemia [106,107], free radical exposure [45,108], N-methyl-D-aspartate toxicity [109], hypoxia [110,111], β-amyloid toxicity [112][113][114], DNA damage [31, 41,110,115], metabotropic receptor signaling [38,116,117], cell metabolic pathways [42,63], and oxidative stress [31,33,41] increases cell survival. Cytoprotection through Akt also can involve control of inflammatory cell activation [33, 41,61], transcription factor regulation [118], maintenance of mitochondrial membrane potential (ΔΨ m ), prevention of cytochrome c release [45,61,105], and blockade of caspase activity [45,61,110] In addition to targeting the activity of membrane PS exposure and microglial activation, nicotinamide inhibits several pro-inflammatory cytokines, such as interleukin-1β, interleukin-6, interleukin-8, tissue factor, and tumor necrosis factor-α (TNF-α) [119][120][121][122].…”