Patients with diabetes are vulnerable to MI/R (myocardial ischaemia/reperfusion) injury, but are not responsive to IPostC (ischaemic post-conditioning) which activates PI3K (phosphoinositide 3-kinase)/Akt (also known as PKB or protein kinase B) and JAK2 (Janus kinase 2)/STAT3 (signal transducer and activator of transcription 3) pathways to confer cardioprotection. We hypothesized that increased cardiac PTEN (phosphatase and tensin homologue deleted on chromosome 10), a major negative regulator of PI3K/Akt, is responsible for the loss of diabetic heart sensitivity to IPostC cardioprotecton. In STZ (streptozotocin)-induced Type 1 diabetic rats subjected to MI/R (30 min coronary occlusion and 120 min reperfusion), the post-ischaemic myocardial infarct size, CK-MB (creatine kinase-MB) and 15-F2t-isoprostane release, as well as cardiac PTEN expression were significantly higher than those in non-diabetic controls, concomitant with more severe cardiac dysfunction and lower cardiac Akt, STAT3 and GSK-3β (glycogen synthase kinase 3β) phosphorylation. IPostC significantly attenuated post-ischaemic infarct size, decreased PTEN expression and further increased Akt, STAT3 and GSK-3β phosphorylation in non-diabetic, but not in diabetic rats. Application of the PTEN inhibitor BpV (bisperoxovanadium) (1.0 mg/kg) restored IPostC cardioprotection in diabetic rats. HPostC (hypoxic post-conditioning) in combination with PTEN gene knockdown, but not HPostC alone, significantly reduced H/R (hypoxia/reoxygenation) injury in cardiac H9c2 cells exposed to high glucose as was evident from reduced apoptotic cell death and JC-1 monomer in cells, accompanied by increased phosphorylation of Akt, STAT3 and GSK-3β. PTEN inhibition/gene knockdown mediated restoration of IPostC/HPostC cardioprotection was completely reversed by the PI3K inhibitor wortmannin, and partially reversed by the JAK2 inhibitor AG490. Increased cardiac PTEN, by impairing PI3K/Akt and JAK2/STAT3 pathways, is a major mechanism that rendered diabetic hearts not responsive to post-conditioning cardioprotection.
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Cover Image
Cover Image
Image of immunofluroscence staining of mouse gonads (left – testis and right – ovary) attached to the mesonephros from between embryonic day 12 and 13. Green indicates the sertoli cell protein Anti-Mullerain Hormone (AMH) and red indicates the ovarian protein called Foxl2. Blue indicates DAPI (which stains the nucleus). The antibodies are AMH (MIS) E19 santa Cruz, sc-34833 and Foxl2 Novus NB100-1277. For further details please see pp. 421-432. The image was kindly generated and provided by I. Knarston, K. Ayers and A. Sinclair.
Research Article|
January 26 2016
Selective inhibition of PTEN preserves ischaemic post-conditioning cardioprotection in STZ-induced Type 1 diabetic rats: role of the PI3K/Akt and JAK2/STAT3 pathways
Rui Xue;
Rui Xue
1
*Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
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Shaoqing Lei;
Shaoqing Lei
1
*Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
†Department of Anesthesiology, the Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
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Zhong-yuan Xia;
*Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
Correspondence: Dr Zhong-yuan Xia (email xiazhongyuan2005@aliyun.com).
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Yang Wu;
Yang Wu
*Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
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Qingtao Meng;
Qingtao Meng
*Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
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Liying Zhan;
Liying Zhan
*Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
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Wating Su;
Wating Su
*Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
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Huimin Liu;
Huimin Liu
*Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
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Jinjin Xu;
Jinjin Xu
*Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
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Zhenzhen Liu;
Zhenzhen Liu
‡Department of Anesthesiology, Renmin Hospital, Nanhai District, Foshan, Guangdong, China
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Bin Zhou;
Bin Zhou
*Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
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Zhengyuan Xia
Zhengyuan Xia
†Department of Anesthesiology, the Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
§Department of Anesthesiology, University of Hong Kong, Hong Kong, China
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Publisher: Portland Press Ltd
Received:
July 13 2015
Revision Received:
November 30 2015
Accepted:
December 14 2015
Accepted Manuscript online:
December 14 2015
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© 2016 Authors; published by Portland Press Limited
2016
Clin Sci (Lond) (2016) 130 (5): 377–392.
Article history
Received:
July 13 2015
Revision Received:
November 30 2015
Accepted:
December 14 2015
Accepted Manuscript online:
December 14 2015
Citation
Rui Xue, Shaoqing Lei, Zhong-yuan Xia, Yang Wu, Qingtao Meng, Liying Zhan, Wating Su, Huimin Liu, Jinjin Xu, Zhenzhen Liu, Bin Zhou, Zhengyuan Xia; Selective inhibition of PTEN preserves ischaemic post-conditioning cardioprotection in STZ-induced Type 1 diabetic rats: role of the PI3K/Akt and JAK2/STAT3 pathways. Clin Sci (Lond) 1 March 2016; 130 (5): 377–392. doi: https://doi.org/10.1042/CS20150496
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