Lin28a protects against cardiac ischaemia/reperfusion injury in diabetic mice through the insulin‐PI3K‐mTOR pathway

Published on Jun 1, 2015in Journal of Cellular and Molecular Medicine4.658
· DOI :10.1111/jcmm.12369
Mingming Zhang12
Estimated H-index: 12
(Fourth Military Medical University),
Dongdong Sun19
Estimated H-index: 19
(Fourth Military Medical University)
+ 7 AuthorsHaichang Wang34
Estimated H-index: 34
(Fourth Military Medical University)
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.
  • References (28)
  • Citations (16)
📖 Papers frequently viewed together
4 Citations
16 Authors (Hao Zhu, ..., George Q. Daley)
515 Citations
1 Citations
78% of Scinapse members use related papers. After signing in, all features are FREE.
#1Barbara A. Miller (PSU: Pennsylvania State University)H-Index: 34
#2Nicholas E. Hoffman (TU: Temple University)H-Index: 20
Last. Joseph Y. CheungH-Index: 43
view all 17 authors...
Cardiac TRPM2 channels were activated by intracellular adenosine diphosphate-ribose and blocked by flufenamic acid. In adult cardiac myocytes the ratio of GCa to GNa of TRPM2 channels was 0.56 ± 0.02. To explore the cellular mechanisms by which TRPM2 channels protect against cardiac ischemia/reperfusion (I/R) injury, we analyzed proteomes from WT and TRPM2 KO hearts subjected to I/R. The canonical pathways that exhibited the largest difference between WT-I/R and KO-I/R hearts were mitochondrial ...
53 CitationsSource
#1Owen L. Woodman (RMIT: RMIT University)H-Index: 28
#2R. Long (French Institute of Health and Medical Research)H-Index: 1
Last. D. Morin (French Institute of Health and Medical Research)H-Index: 1
view all 6 authors...
Abstract The study aimed to determine the effect of 3′,4′-dihydroxyflavonol (DiOHF) on mitochondrial function, in particular opening of the mitochondrial permeability transition pore (mPTP), respiratory function and reactive oxygen species (ROS) production, in isolated cardiac mitochondria after coronary artery occlusion and reperfusion in vivo. Opening of the mPTP, oxygen consumption and ROS production (assessed by measurement of H 2 O 2 ) was determined in mitochondria isolated from normal hea...
12 CitationsSource
#1Tara M. Henagan (Purdue University)H-Index: 14
#2Natalie R. Lenard (Our Lady of the Lake College)H-Index: 14
Last. Laura K. Stewart (LSU: Louisiana State University)H-Index: 20
view all 4 authors...
Aims/Hypothesis High fat diet (HFD)-induced insulin resistance (IR) is partially characterized by reduced skeletal muscle mitochondrial function and peroxisome proliferator activated receptor gamma coactivator 1 alpha (PGC1α) expression. Our previous study showed that a high dose of the bioflavonoid quercetin exacerbated HFD-induced IR; yet, others have demonstrated that quercetin improves insulin sensitivity. The aim of this study was to investigate whether differing doses of quercetin act in a...
30 CitationsSource
#1Jonas M. Kristensen (UCPH: University of Copenhagen)H-Index: 12
#2Vibe Skov (OUH: Odense University Hospital)H-Index: 10
Last. Kurt Højlund (UCPH: University of Copenhagen)H-Index: 43
view all 7 authors...
Aims/hypothesis Insulin resistance in obesity and type 2 diabetes is related to abnormalities in mitochondrial oxidative phosphorylation (OxPhos) in skeletal muscle. We tested the hypothesis that mitochondrial oxidative metabolism is impaired in muscle of patients with inherited insulin resistance and defective insulin signalling.
20 CitationsSource
#1Tara SpenceH-Index: 5
#2Christian PerottiH-Index: 14
Last. Jennifer AngH-Index: 53
view all 15 authors...
Background Embryonal tumor with multilayered rosettes (ETMR) is an aggressive central nervous system primitive neuroectodermal tumor (CNS-PNET) variant. ETMRs have distinctive histology, amplification of the chromosome 19 microRNA cluster (C19MC) at chr19q13.41-42, expression of the RNA binding protein Lin28, and dismal prognosis. Functional and therapeutic studies of ETMR have been limited by a lack of model systems.
29 CitationsSource
#1Ng Shyh-ChangH-Index: 22
#2Hao ZhuH-Index: 23
Last. George Q. DaleyH-Index: 108
view all 10 authors...
Summary Regeneration capacity declines with age, but why juvenile organisms show enhanced tissue repair remains unexplained. Lin28a , a highly conserved RNA-binding protein expressed during embryogenesis, plays roles in development, pluripotency, and metabolism. To determine whether Lin28a might influence tissue repair in adults, we engineered the reactivation of Lin28a expression in several models of tissue injury. Lin28a reactivation improved hair regrowth by promoting anagen in hair follicles...
180 CitationsSource
#1Gen Shinoda (Harvard University)H-Index: 7
#2Ng Shyh-Chang (Harvard University)H-Index: 22
Last. George Q. Daley (Harvard University)H-Index: 108
view all 14 authors...
LIN28A/B are RNA binding proteins implicated by genetic association studies in human growth and glucose metabolism. Mice with ectopic over-expression of Lin28a have shown related phenotypes. Here, we describe the first comprehensive analysis of the physiologic consequences of Lin28a and Lin28b deficiency in knockout (KO) mice. Lin28a/b-deficiency led to dwarfism starting at different ages, and compound gene deletions showed a cumulative dosage effect on organismal growth. Conditional gene deleti...
63 CitationsSource
#1James E. Thornton (Harvard University)H-Index: 7
#2Richard I. Gregory (Harvard University)H-Index: 37
One of the most ancient and highly conserved microRNAs (miRNAs), the let-7 family, has gained notoriety owing to its regulation of stem cell differentiation and essential role in normal development, as well as its tumor suppressor function. Mechanisms controlling let-7 expression have recently been uncovered, specifically the role of the RNA-binding protein Lin28 – a key developmental regulator – in blocking let-7 biogenesis. This review focuses on our current understanding of the Lin28-mediated...
214 CitationsSource
#1Dongdong Sun (Fourth Military Medical University)H-Index: 19
#2Jie HuangH-Index: 1
Last. Haichang Wang (Fourth Military Medical University)H-Index: 34
view all 8 authors...
Background The present study was to investigate the effects and mechanism of Luteolin on myocardial infarct size, cardiac function and cardiomyocyte apoptosis in diabetic rats with myocardial ischemia/reperfusion (I/R) injury. Methodology/Principal Findings Diabetic rats underwent 30 minutes of ischemia followed by 3 h of reperfusion. Animals were pretreated with or without Luteolin before coronary artery ligation. The severity of myocardial I/R induced LDH release, arrhythmia, infarct size, car...
63 CitationsSource
#1Hao ZhuH-Index: 23
#2Ng Shyh-Chang (Harvard University)H-Index: 22
Last. George Q. DaleyH-Index: 108
view all 16 authors...
515 CitationsSource
Cited By16
#1Peng-Hua You (Fourth Military Medical University)H-Index: 1
#2Zheng Cheng (Fourth Military Medical University)
Last. Gong ChengH-Index: 1
view all 7 authors...
Lin28a has been found to enhance glucose uptake and insulin sensitivity. Lin28a alleviates cardiac dysfunction under various pathological conditions. However, the effects and underlying mechanisms of Lin28a on diabetic cardiomyopathy (DCM) are not well-understood. The aim of this study was to determine whether Lin28a protects against DCM and the potential mechanisms. Two to three days old mouse neonatal primary cardiomyocytes were randomized for treatment with adenoviruses harboring Lin28a and m...
#1Antonio CrisafulliH-Index: 22
#2Pasquale Pagliaro (UNITO: University of Turin)H-Index: 36
Last. Manuela AragnoH-Index: 36
view all 11 authors...
Metabolic syndrome, diabetes, and ischemic heart disease are among the leading causes of death and disability in Western countries. Diabetic cardiomyopathy is responsible for the most severe signs and symptoms. An important strategy for reducing the incidence of cardiovascular disease is regular exercise. Remote ischemic conditioning has some similarity with exercise and can be induced by short periods of ischemia and reperfusion of a limb, and it can be performed in people who cannot exercise. ...
1 CitationsSource
#1Tingting Wang (Fourth Military Medical University)H-Index: 6
#2Chuang Sun (Fourth Military Medical University)H-Index: 1
Last. Dongdong Sun (Fourth Military Medical University)H-Index: 19
view all 7 authors...
Sirt6 has been reported to play a protective role in macrophage foam cell formation, but whether Sirt6 controls atherosclerosis plaque stability and whether it can reduce the interaction between en...
1 CitationsSource
#1Tao Zhang (HUST: Huazhong University of Science and Technology)H-Index: 3
#2Jianrong Guo (HUST: Huazhong University of Science and Technology)H-Index: 2
Last. Jiliang Wang (HUST: Huazhong University of Science and Technology)H-Index: 6
view all 6 authors...
Liver ischemia/reperfusion (IR) injury is a common phenomenon after liver resection and transplantation, which often results in liver graft dysfunction such as delayed graft function and primary nonfunction. The mammalian target of rapamycin (mTOR) is an evolutionarily highly conserved serine/threonine protein kinase, which coordinates cell growth and metabolism through sensing environmental inputs under physiological or pathological conditions, involved in the pathophysiological process of IR i...
2 CitationsSource
#1Liping Wei (NKU: Nankai University)H-Index: 1
#2Xuseng Sun (Tianjin Medical University)H-Index: 1
Last. Yue Xu (Tianjin University of Traditional Chinese Medicine)H-Index: 1
view all 6 authors...
During myocardial infarction, quickly opening the occluded coronary artery is a major method to save the ischemic myocardium. However, it also induces reperfusion injury, resulting in a poor prognosis. Alleviating the reperfusion injury improves the prognosis of the patients. Dihydromyricetin (DHM), a major component in the Ampelopsis grossedentata, has numerous biological functions. This study aims to clarify the effects of DHM under the ischemia/reperfusion (I/R) condition. We elucidated the r...
2 CitationsSource
#1Sakshi Tyagi (Punjabi University)H-Index: 1
#2Nirmal Singh (Punjabi University)H-Index: 35
Last. Amteshwar Singh Jaggi (Punjabi University)H-Index: 33
view all 4 authors...
Diabetes mellitus significantly hampers the development of cardioprotective response to remote pre/post/perconditioning stimuli by impairing the activation of cardioprotective signaling pathways. Among the different pathways, the impairment in O-linked β-N-acetylglucosamine (O-GlcNAc) signaling and release of cardioprotective humoral factor may contribute in attenuating remote preconditioning-induced cardioprotection. Moreover, the failure to phosphorylate extracellular signal related kinase (ER...
3 CitationsSource
#1Arun Samidurai (VCU: Virginia Commonwealth University)H-Index: 8
#2Rakesh C. Kukreja (VCU: Virginia Commonwealth University)H-Index: 58
Last. Anindita Das (VCU: Virginia Commonwealth University)H-Index: 33
view all 3 authors...
Mechanistic/mammalian target of rapamycin (mTOR), an atypical serine/threonine kinase of the phosphoinositide 3-kinase- (PI3K-) related kinase family, elicits a vital role in diverse cellular processes, including cellular growth, proliferation, survival, protein synthesis, autophagy, and metabolism. In the cardiovascular system, the mTOR signaling pathway integrates both intracellular and extracellular signals and serves as a central regulator of both physiological and pathological processes. Mi...
2 CitationsSource
#1Curtis A. Nutter (UTMB: University of Texas Medical Branch)H-Index: 5
#2Muge N. Kuyumcu-Martinez (UTMB: University of Texas Medical Branch)H-Index: 7
: Diabetes is a debilitating health care problem affecting 422 million people around the world. Diabetic patients suffer from multisystemic complications that can cause mortality and morbidity. Recent advancements in high-throughput next-generation RNA-sequencing and computational algorithms led to the discovery of aberrant posttranscriptional gene regulatory programs in diabetes. However, very little is known about how these regulatory programs are mis-regulated in diabetes. RNA-binding protein...
5 CitationsSource
#1Shuang Li (Chinese PLA General Hospital)H-Index: 2
#2Hao Wu (Fourth Military Medical University)H-Index: 3
Last. Feng Cao (Chinese PLA General Hospital)H-Index: 37
view all 13 authors...
Coronary heart disease patients with type 2 diabetes were subject to higher vulnerability for cardiac ischemia-reperfusion (I/R) injury. This study was designed to evaluate the impact of ZP2495 (a glucagon-GLP-1 dual-agonist) on cardiac function and energy metabolism after myocardial I/R injury in db/db mice with a focus on mitochondrial function. C57BLKS/J-lepr
1 CitationsSource
#1Haibo Chen (Peking Union Medical College)H-Index: 1
#2Si Liu (Peking Union Medical College)H-Index: 2
Last. Xi Chen (Peking Union Medical College)H-Index: 14
view all 7 authors...
The cardioprotection of the immature heart during cardiac surgery remains controversial due to the differences between the adult heart and the newborn heart. Lysophosphatidic acid (LPA) is a small bioactive molecule with diverse functions including cell proliferation and survival via its receptor: LPA1-LPA6. We previously reported that the expressions of LPA1 and LPA3 in rat hearts were much higher in immature hearts and then declined rapidly with age. In this study, we aimed to investigate whet...
8 CitationsSource