title: 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.
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.
authors.affiliation: Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Xue
authors.affiliation: 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.
authors.forename: Shaoqing
authors.initials: S
authors.lastname: Lei
authors.affiliation: Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China xiazhongyuan2005@aliyun.com.
authors.forename: Zhong-yuan
authors.initials: ZY
authors.lastname: Xia
authors.affiliation: Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China.
authors.forename: Qingtao
authors.initials: Q
authors.lastname: Meng
authors.affiliation: Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China.
authors.forename: Liying
authors.initials: L
authors.lastname: Zhan
authors.affiliation: Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China.
authors.forename: Wating
authors.initials: W
authors.lastname: Su
authors.affiliation: Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China.
authors.forename: Huimin
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China.
authors.forename: Jinjin
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Anesthesiology, Renmin Hospital, Nanhai District, Foshan, Guangdong, China.
authors.forename: Zhenzhen
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhou
authors.affiliation: 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.
authors.forename: Zhengyuan
authors.initials: Z
authors.lastname: Xia
mesh_terms: D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000150:complications* / Q000378:metabolism; D055785:Gene Knockdown Techniques / Q000379:methods; D057775:Ischemic Postconditioning / Q000379:methods*; D053614:Janus Kinase 2 / Q000502:physiology; D008297:Male; D009203:Myocardial Infarction / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D058539:Phosphatidylinositol 3-Kinase / Q000502:physiology; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D034741:RNA, Small Interfering / Q000235:genetics; D017207:Rats, Sprague-Dawley; D050796:STAT3 Transcription Factor / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D017968:Vanadium Compounds / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D017968:Vanadium Compounds; C472777:bisperoxovanadium; D058539:Phosphatidylinositol 3-Kinase; C507927:Jak2 protein, rat; D053614:Janus Kinase 2; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C487216:Pten protein, rat
keywords: diabetes; ischaemic post-conditioning; myocardial ischaemia/reperfusion injury; phosphatase and tensin homologue deleted on chromosome 10 (PTEN)