title: Lin28a protects against cardiac ischaemia/reperfusion injury in diabetic mice through the insulin-PI3K-mTOR pathway.
abstract: The insulin-PI3K-mTOR pathway exhibits a variety of cardiovascular activities including protection against I/R injury. Lin28a enhanced glucose uptake and insulin-sensitivity via insulin-PI3K-mTOR signalling pathway. However, the role of lin28a on experimental cardiac I/R injury in diabetic mice are not well understood. Diabetic mice underwent 30 min. of ischaemia followed by 3 hrs of reperfusion. Animals were randomized to be treated with lentivirus carrying lin28a siRNA (siLin28a) or lin28a cDNA (Lin28a) 72 hrs before coronary artery ligation. Myocardial infarct size (IS), cardiac function, cardiomyocyte apoptosis and mitochondria morphology in diabetic mice who underwent cardiac I/R injury were compared between groups. The target proteins of lin28a were examined by western blot analysis. Lin28a overexpression significantly reduced myocardial IS, improved LV ejection fraction (LVEF), decreased myocardial apoptotic index and alleviated mitochondria cristae destruction in diabetic mice underwent cardiac I/R injury. Lin28a knockdown exacerbated cardiac I/R injury as demonstrated by increased IS, decreased LVEF, increased apoptotic index and aggravated mitochondria cristae destruction. Interestingly, pre-treatment with rapamycin abolished the beneficial effects of lin28a overexpression. Lin28a overexpression increased, while Lin28a knockdown decreased the expression of IGF1R, p-Akt, p-mTOR and p-p70s6k after cardiac I/R injury in diabetic mice. Rapamycin pre-treatment abolished the effects of increased p-mTOR and p-p70s6k expression exerted by lin28a overexpression. This study indicates that lin28a overexpression reduces IS, improves cardiac function, decreases cardiomyocyte apoptosis index and alleviates cardiomyocyte mitochondria impairment after cardiac I/R injury in diabetic mice. The mechanism responsible for the effects of lin28a is associated with the insulin-PI3K-mTOR dependent pathway.
authors: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors: Mingming
authors: M
authors: Zhang
authors: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors: Dongdong
authors: D
authors: Sun
authors: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors: Shuang
authors: S
authors: Li
authors: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors: Xietian
authors: X
authors: Pan
authors: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors: Xiaotian
authors: X
authors: Zhang
authors: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors: Di
authors: D
authors: Zhu
authors: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors: Congye
authors: C
authors: Li
authors: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors: Rongqing
authors: R
authors: Zhang
authors: Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA, USA.
authors: Erhe
authors: E
authors: Gao
authors: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors: Haichang
authors: H
authors: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D016207:Cytokines / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D015870:Gene Expression; D006321:Heart / Q000503:physiopathology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology*; D008297:Male; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D020011:Protective Agents / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D016207:Cytokines; D007004:Hypoglycemic Agents; D007328:Insulin; D035683:MicroRNAs; D019869:Phosphatidylinositol 3-Kinases; D020011:Protective Agents; D051057:Proto-Oncogene Proteins c-akt; D016601:RNA-Binding Proteins; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; C488352:Lin-28 protein, mouse; C542687:mirnlet7 microRNA, mouse; C546843:mTOR protein, mouse
keywords: Lin28a; diabetes; ischaemia/reperfusion injury