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Recombinant Human Erythropoietin Protects Myocardial Cells from Apoptosis via the Janus-Activated Kinase 2/Signal Transducer and Activator of Transcription 5 Pathway in Rats with Epilepsy.

Ma BX, Li J, Li H, Wu SS - Curr Ther Res Clin Exp (2015)

Bottom Line: At different time points after seizure onset, electroencephalogram changes were recorded, and myocardium samples were taken for the detection of myocardial cell apoptosis and expression of JAK2, signal transducer and activator of transcription 5 (STAT5), caspase-3, and bcl-xl mRNAs and proteins.Induction of epilepsy significantly enhanced myocardial cell apoptosis and upregulated the expression of caspase-3 and bcl-xl proteins and JAK2 and STAT5a at both the mRNA and protein levels.These results indicate that myocardial cell apoptosis may contribute to myocardial injury in epilepsy.

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiology, Affiliated Hospital of Binzhou Medical University, Binzhou, China.

ABSTRACT

Objective: To investigate the potential mechanisms underlying the protective effects of recombinant human erythropoietin (rhEPO) and carbamylated EPO (CEPO) against myocardial cell apoptosis in epilepsy.

Methods: Rats were given an intra-amygdala injection of kainic acid to induce epilepsy. Groups of rats were treated with rhEPO or CEPO before induction of epilepsy, whereas additional rats were given a caudal vein injection of AG490, a selective inhibitor of Janus kinase 2 (JAK2). At different time points after seizure onset, electroencephalogram changes were recorded, and myocardium samples were taken for the detection of myocardial cell apoptosis and expression of JAK2, signal transducer and activator of transcription 5 (STAT5), caspase-3, and bcl-xl mRNAs and proteins.

Results: Induction of epilepsy significantly enhanced myocardial cell apoptosis and upregulated the expression of caspase-3 and bcl-xl proteins and JAK2 and STAT5a at both the mRNA and protein levels. Pretreatment with either rhEPO or CEPO reduced the number of apoptotic cells, upregulated bcl-xl expression, and downregulated caspase-3 expression in the myocardium of epileptic rats. Both myocardial JAK2 and STAT5a mRNAs, as well as phosphorylated species of JAK2 and STAT5a, were upregulated in epileptic rats in response to rhEPO-but not to CEPO-pretreatment. AG490 treatment increased apoptosis, upregulated caspase-3 protein expression, and downregulated bcl-xl protein expression in the myocardium of epileptic rats.

Conclusions: These results indicate that myocardial cell apoptosis may contribute to myocardial injury in epilepsy. EPO protects myocardial cells from apoptosis via the JAK2/STAT5 pathway in rats with experimental epilepsy, whereas CEPO exerts antiapoptotic activity perhaps via a pathway independent of JAK2/STAT5 signaling.

No MeSH data available.


Related in: MedlinePlus

Recombinant human erythropoietin (rhEPO) and carbamylated erythropoietin (CEPO) upregulate expression of bcl-xl protein in the myocardium of rats with kainic acid-induced epilepsy. Myocardial bcl-xl protein expression was determined by immunohistochemistry at 0, 2, 6, 12, and 24 hours after the onset of seizures. Representative images (400×; 24 hours after onset of seizures) of bcl-xl expression in the myocardium of (A) control and (B) epileptic rats and epileptic rats treated with (C) ethanol, (D) rhEPO, (E) CEPO, or (F) AG490. The cytoplasm of positive cells is stained brown (shown by arrows).
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f0025: Recombinant human erythropoietin (rhEPO) and carbamylated erythropoietin (CEPO) upregulate expression of bcl-xl protein in the myocardium of rats with kainic acid-induced epilepsy. Myocardial bcl-xl protein expression was determined by immunohistochemistry at 0, 2, 6, 12, and 24 hours after the onset of seizures. Representative images (400×; 24 hours after onset of seizures) of bcl-xl expression in the myocardium of (A) control and (B) epileptic rats and epileptic rats treated with (C) ethanol, (D) rhEPO, (E) CEPO, or (F) AG490. The cytoplasm of positive cells is stained brown (shown by arrows).

Mentions: To examine whether bcl-xl protein expression in the myocardium is altered and whether EPO and CEPO affect such alteration in epileptic rats, immunohistochemistry was performed. As shown in Figure 5, bcl-xl protein was expressed at comparatively low levels in the myocardium of normal rats. No significant difference was noted in the expression intensity of bcl-xl protein between the normal control group and PBS group (P > 0.05). In the epilepsy group, the expression of bcl-xl protein in the myocardium began to be upregulated rapidly 2 hours after the onset of seizures. The expression intensity of bcl-xl protein increased with time, peaking at 24 hours. The expression intensity of bcl-xl protein at 24 hours was significantly higher in the epilepsy group than in the PBS group (P < 0.01). Pretreatment with either EPO or CEPO further enhanced the expression of bcl-xl protein in epileptic rats, and the expression intensity of bcl-xl protein increased with time, peaking at 24 hours. The expression intensity of bcl-xl protein at 24 hours was significantly higher in the EPO and CEPO groups than in the epilepsy group (both P values < 0.01). AG490 treatment reduced the expression of bcl-xl protein in epileptic rats, and the expression intensity of bcl-xl protein decreased with time, reaching lowest levels at 24 hours. The expression intensity of bcl-xl protein at 24 hours was significantly lower in the AG490 group than in the ethanol group (P < 0.01). Additionally, the expression intensity of bcl-xl protein at 2, 6, 12, and 24 hours was significantly lower in the AG490 group than in the EPO and CEPO groups (all P values < 0.01).


Recombinant Human Erythropoietin Protects Myocardial Cells from Apoptosis via the Janus-Activated Kinase 2/Signal Transducer and Activator of Transcription 5 Pathway in Rats with Epilepsy.

Ma BX, Li J, Li H, Wu SS - Curr Ther Res Clin Exp (2015)

Recombinant human erythropoietin (rhEPO) and carbamylated erythropoietin (CEPO) upregulate expression of bcl-xl protein in the myocardium of rats with kainic acid-induced epilepsy. Myocardial bcl-xl protein expression was determined by immunohistochemistry at 0, 2, 6, 12, and 24 hours after the onset of seizures. Representative images (400×; 24 hours after onset of seizures) of bcl-xl expression in the myocardium of (A) control and (B) epileptic rats and epileptic rats treated with (C) ethanol, (D) rhEPO, (E) CEPO, or (F) AG490. The cytoplasm of positive cells is stained brown (shown by arrows).
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4644243&req=5

f0025: Recombinant human erythropoietin (rhEPO) and carbamylated erythropoietin (CEPO) upregulate expression of bcl-xl protein in the myocardium of rats with kainic acid-induced epilepsy. Myocardial bcl-xl protein expression was determined by immunohistochemistry at 0, 2, 6, 12, and 24 hours after the onset of seizures. Representative images (400×; 24 hours after onset of seizures) of bcl-xl expression in the myocardium of (A) control and (B) epileptic rats and epileptic rats treated with (C) ethanol, (D) rhEPO, (E) CEPO, or (F) AG490. The cytoplasm of positive cells is stained brown (shown by arrows).
Mentions: To examine whether bcl-xl protein expression in the myocardium is altered and whether EPO and CEPO affect such alteration in epileptic rats, immunohistochemistry was performed. As shown in Figure 5, bcl-xl protein was expressed at comparatively low levels in the myocardium of normal rats. No significant difference was noted in the expression intensity of bcl-xl protein between the normal control group and PBS group (P > 0.05). In the epilepsy group, the expression of bcl-xl protein in the myocardium began to be upregulated rapidly 2 hours after the onset of seizures. The expression intensity of bcl-xl protein increased with time, peaking at 24 hours. The expression intensity of bcl-xl protein at 24 hours was significantly higher in the epilepsy group than in the PBS group (P < 0.01). Pretreatment with either EPO or CEPO further enhanced the expression of bcl-xl protein in epileptic rats, and the expression intensity of bcl-xl protein increased with time, peaking at 24 hours. The expression intensity of bcl-xl protein at 24 hours was significantly higher in the EPO and CEPO groups than in the epilepsy group (both P values < 0.01). AG490 treatment reduced the expression of bcl-xl protein in epileptic rats, and the expression intensity of bcl-xl protein decreased with time, reaching lowest levels at 24 hours. The expression intensity of bcl-xl protein at 24 hours was significantly lower in the AG490 group than in the ethanol group (P < 0.01). Additionally, the expression intensity of bcl-xl protein at 2, 6, 12, and 24 hours was significantly lower in the AG490 group than in the EPO and CEPO groups (all P values < 0.01).

Bottom Line: At different time points after seizure onset, electroencephalogram changes were recorded, and myocardium samples were taken for the detection of myocardial cell apoptosis and expression of JAK2, signal transducer and activator of transcription 5 (STAT5), caspase-3, and bcl-xl mRNAs and proteins.Induction of epilepsy significantly enhanced myocardial cell apoptosis and upregulated the expression of caspase-3 and bcl-xl proteins and JAK2 and STAT5a at both the mRNA and protein levels.These results indicate that myocardial cell apoptosis may contribute to myocardial injury in epilepsy.

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiology, Affiliated Hospital of Binzhou Medical University, Binzhou, China.

ABSTRACT

Objective: To investigate the potential mechanisms underlying the protective effects of recombinant human erythropoietin (rhEPO) and carbamylated EPO (CEPO) against myocardial cell apoptosis in epilepsy.

Methods: Rats were given an intra-amygdala injection of kainic acid to induce epilepsy. Groups of rats were treated with rhEPO or CEPO before induction of epilepsy, whereas additional rats were given a caudal vein injection of AG490, a selective inhibitor of Janus kinase 2 (JAK2). At different time points after seizure onset, electroencephalogram changes were recorded, and myocardium samples were taken for the detection of myocardial cell apoptosis and expression of JAK2, signal transducer and activator of transcription 5 (STAT5), caspase-3, and bcl-xl mRNAs and proteins.

Results: Induction of epilepsy significantly enhanced myocardial cell apoptosis and upregulated the expression of caspase-3 and bcl-xl proteins and JAK2 and STAT5a at both the mRNA and protein levels. Pretreatment with either rhEPO or CEPO reduced the number of apoptotic cells, upregulated bcl-xl expression, and downregulated caspase-3 expression in the myocardium of epileptic rats. Both myocardial JAK2 and STAT5a mRNAs, as well as phosphorylated species of JAK2 and STAT5a, were upregulated in epileptic rats in response to rhEPO-but not to CEPO-pretreatment. AG490 treatment increased apoptosis, upregulated caspase-3 protein expression, and downregulated bcl-xl protein expression in the myocardium of epileptic rats.

Conclusions: These results indicate that myocardial cell apoptosis may contribute to myocardial injury in epilepsy. EPO protects myocardial cells from apoptosis via the JAK2/STAT5 pathway in rats with experimental epilepsy, whereas CEPO exerts antiapoptotic activity perhaps via a pathway independent of JAK2/STAT5 signaling.

No MeSH data available.


Related in: MedlinePlus