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A soluble receptor for advanced glycation end-products inhibits myocardial apoptosis induced by ischemia/reperfusion via the JAK2/STAT3 pathway

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Abstract

sRAGE can protect cardiomyocytes from apoptosis induced by ischemia/reperfusion (I/R). However, the signaling mechanisms in cardioprotection by sRAGE are currently unknown. We investigated the cardioprotective effect and potential molecular mechanisms of sRAGE inhibition on apoptosis in the mouse myocardial I/R as an in vivo model and neonatal rat cardiomyocyte subjected to ischemic buffer as an in vitro model. Cardiac function and myocardial infarct size following by I/R were evaluated with echocardiography and Evans blue/2,3,5-triphenyltetrazolium chloride. Apoptosis was detected by TUNEL staining and caspase-3 activity. Expression of the apoptosis-related proteins p53, Bax, Bcl-2, JAK2/p-JAK2, STAT3/p-STAT3, AKT/p-AKT, ERK/p-ERK, STAT5A/p-STAT5A and STAT6/p-STAT6 were detected by western blot analysis in the presence and absence of the JAK2 inhibitor AG 490. sRAGE (100 µg/day) improved the heart function in mice with I/R: the left ventricular ejection fraction and fractional shortening were increased by 42 and 57 %, respectively; the infarct size was decreased by 52 %, the TUNEL-positive myocytes by 66 %, and activity of caspase-3 by 24 %, the protein expression of p53 and ratio of Bax to Bcl-2 by 29 and 88 %, respectively; protein expression of the p-JAK2, p-STAT3 and p-AKT were increased by 92, 280 and 31 %, respectively. sRAGE have no effect on protein expression of p-ERK1/2, p-STAT5A and p-STAT6 following by I/R. sRAGE (900 nmol/L) exhibited anti-apoptotic effects in cardiomyocytes by decreasing TUNEL-positive myocytes by 67 % and caspase-3 activity by 20 %, p53 protein level and the Bax/Bcl-2 ratio by 58 and 86 %, respectively; increasing protein expression of the p-JAK2 and p-STAT3 by 26 and 156 %, respectively, p-AKT protein level by 33 %. The anti-apoptotic effects of sRAGE following I/R were blocked by JAK2 inhibitor AG 490. The effect of sRAGE reduction on TUNEL-positive myocytes and caspase-3 activity were abolished by PI3K inhibitor LY294002, but not ERK 1/2 inhibitor PD98059. These results suggest that sRAGE protects cardiomyocytes from apoptosis induced by I/R in vitro and in vivo by activating the JAK2/STAT3 signaling pathway.

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Abbreviations

sRAGE:

Soluble receptor for advanced glycation end-products

I/R:

Ischemia/reperfusion

JAK/STAT:

Janus kinase/signal transducer and activator of transcription

JAK2:

Janus activated kinase 2

STAT3:

Signal transducer and activator of transcription 3

RAGE:

Receptor for advanced glycation end-products

EF:

Ejection fraction

FS:

Fractional shortening

LV:

Left ventricular

ERK ½:

Extracellular signal-regulated kinase 1/2

PI3K:

Phosphatidylinositol 3 kinase

AKT:

Protein kinase B

TTC:

2,3,5-Triphenyltetrazolium chloride

TUNEL:

Terminal deoxynucleotidyl transferase-mediated nick end label

Bax:

Bcl-2-associated X protein

Bcl-2:

B-cell lymphoma 2

DMEM:

Dulbecco’s modified eagle medium

DMSO:

Dimethyl sulfoxide

FBS:

Fatal bovine serum

PBS:

Phosphate buffer saline

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Acknowledgments

This work was supported by the National Natural Science Foundation of China (Grant Nos. 30801217, 81370313), Beijing Nova Program (Grant No. 2010B050) and Beijing Health System High Level Health Technical Personnel Training Program (Grant No. 2013-3-046).

Conflict of interest

We have no competing interest and conflict interest.

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    Authors and Affiliations

    1. Department of Cardiology, Beijing Tian Tan Hospital, Capital Medical University, 6 Tiantan Xili, Dongcheng District, Beijing, 100050, China

      Xue Jiang, Cai-xia Guo, Bu-xing Chen & Feng-he Du

    2. Department of Geriatrics, Beijing Tian Tan Hospital, Capital Medical University, 6 Tiantan Xili, Dongcheng District, Beijing, 100050, China

      Feng-he Du

    3. Department of Physiology and Pathophysiology, Capital Medical University, Beijing, 100069, China

      Xiang-jun Zeng & Hui-hua Li

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    1. Xue Jiang
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    Correspondence to Cai-xia Guo or Feng-he Du.

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    Xue Jiang and Cai-xia Guo have contributed equally to this work.

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    Jiang, X., Guo, Cx., Zeng, Xj. et al. A soluble receptor for advanced glycation end-products inhibits myocardial apoptosis induced by ischemia/reperfusion via the JAK2/STAT3 pathway. Apoptosis 20, 1033–1047 (2015). https://doi.org/10.1007/s10495-015-1130-4

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