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Clin Sci (Lond). 2016 Mar;130(5):377-92. doi: 10.1042/CS20150496. Epub 2015 Dec 14.

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.

Author information

1
Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China.
2
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.
3
Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China xiazhongyuan2005@aliyun.com.
4
Department of Anesthesiology, Renmin Hospital, Nanhai District, Foshan, Guangdong, China.
5
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.

Abstract

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.

KEYWORDS:

diabetes; ischaemic post-conditioning; myocardial ischaemia/reperfusion injury; phosphatase and tensin homologue deleted on chromosome 10 (PTEN)

PMID:
26666444
DOI:
10.1042/CS20150496
[Indexed for MEDLINE]

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