title: Effect of lithium on ventricular remodelling in infarcted rats via the Akt/mTOR signalling pathways.
abstract: Activation of phosphoinositide 3-kinase (PI3K)/Akt signalling is the molecular pathway driving physiological hypertrophy. As lithium, a PI3K agonist, is highly toxic at regular doses, we assessed the effect of lithium at a lower dose on ventricular hypertrophy after myocardial infarction (MI). Male Wistar rats after induction of MI were randomized to either vehicle or lithium (1 mmol/kg per day) for 4 weeks. The dose of lithium led to a mean serum level of 0.39 mM, substantially lower than the therapeutic concentrations (0.8-1.2 mM). Infarction in the vehicle was characterized by pathological hypertrophy in the remote zone; histologically, by increased cardiomyocyte sizes, interstitial fibrosis and left ventricular dilatation; functionally, by impaired cardiac contractility; and molecularly, by an increase of p-extracellular-signal-regulated kinase (ERK) levels, nuclear factor of activated T cells (NFAT) activity,GATA4expression and foetal gene expressions. Lithium administration mitigated pathological remodelling. Furthermore, lithium caused increased phosphorylation of eukaryotic initiation factor 4E binding protein 1 (p-4E-BP1), the downstream target of mammalian target of rapamycin (mTOR). Blockade of the Akt and mTOR signalling pathway with deguelin and rapamycin resulted in markedly diminished levels of p-4E-BP1, but not ERK. The present study demonstrated that chronic lithium treatment at low doses mitigates pathological hypertrophy through an Akt/mTOR dependent pathway.
authors.affiliation: Department of Medicine, Cardiology Section, An Nan Hospital, China Medical University, Tainan, Taiwan.|Department of Medicine, China Medical University, Taichung, Taiwan.|Cardiovascular Research Laboratory, China Medical University Hospital, Taichung, Taiwan.|Division of Cardiology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Tsung-Ming
authors.initials: TM
authors.lastname: Lee
authors.affiliation: Bioinnovation Center, Tzu Chi foundation; Department of Neurosurgery, Buddhist Tzu Chi General hospital, Tzu Chi University, Hualien, Taiwan.
authors.forename: Shinn-Zong
authors.initials: SZ
authors.lastname: Lin
authors.affiliation: Division of Cardiology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan 861003@h.tmu.edu.tw.|Division of Cardiology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan.
authors.forename: Nen-Chung
authors.initials: NC
authors.lastname: Chang
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D004106:Dilatation; D005355:Fibrosis; D050991:GATA4 Transcription Factor / Q000378:metabolism; D006352:Heart Ventricles / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins; D018020:Lithium Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D009200:Myocardial Contraction; D009203:Myocardial Infarction / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D050778:NFATC Transcription Factors / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D012402:Rotenone / Q000031:analogs & derivatives / Q000494:pharmacology; D020123:Sirolimus / Q000494:pharmacology; D013268:Stimulation, Chemical; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D013997:Time Factors; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: D002352:Carrier Proteins; D050991:GATA4 Transcription Factor; D047908:Intracellular Signaling Peptides and Proteins; D018020:Lithium Compounds; D050778:NFATC Transcription Factors; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins; D051057:Proto-Oncogene Proteins c-akt; D012402:Rotenone; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; C499526:Eif4ebp1 protein, rat; C084365:Gata4 protein, rat; C546845:mTOR protein, rat; C107676:deguelin
keywords: Echocardiography; Myocardial infarction; Nuclear factor of activated T-cells; Physiological hypertrophy; Ventricular remodeling