title: Targeting the pathway of GSK-3β/nerve growth factor to attenuate post-infarction arrhythmias by preconditioned adipose-derived stem cells.
abstract: Adipose-derived stem cell (ADSC) transplantation is a promising new therapy to improve cardiac function after myocardial infarction. However, its low efficacy of transdifferentiation hampers its usefulness. Glycogen synthase kinase-3β (GSK-3β) signal has been shown to play a role in preconditioning-induced cardioprotection. We assessed whether n-butylidenephthalide (BP) primed ADSCs can attenuate arrhythmias by a GSK-3β-dependent pathway after myocardial infarction. Male Wistar rats after coronary ligation was randomly allocated to receive intramyocardial injection of vehicle, ADSCs, BP-preconditioned ADSCs, (BP+lithium)-preconditioned ADSCs, (BP+SB216763)-preconditioned ADSCs, and (BP+LY294002)-preconditioned ADSCs. ADSCs were primed for 16h before implantation. After 4weeks of implantation, ADSCs were retained in myocardium, reduced fibrosis and improved cardiac function. Sympathetic hyperinnervation was blunted after administering ADSCs, assessed by immunofluorescent analysis, and Western blotting and real-time quantitative RT-PCR of nerve growth factor. Arrhythmic scores during programmed stimulation in the ADSC-treated infarcted rats were significantly lower than vehicle. BP-preconditioned ADSCs had superior cardioprotection, greater ADSC engraftment and transdifferentiation, and antiarrhythmic effects compared with ADSCs alone. Simultaneously, BP increased the levels of phospho-Akt and down-regulated GSK-3β activity. The effects of BP against sympathetic hyperinnervation were blocked by LY294002, a PI3K inhibitor. Addition of either lithium or SB216763 did not have additional effects compared with BP alone. Compared with ADSC alone, BP-primed ADSC implantation improved stem cell engraftment and attenuated sympathetic hyperinnervation and arrhythmias through a PI3K/Akt/GSK-3β-dependent pathway, suggesting that a synergic action was achieved between BP pretreatment and ADSCs.
authors.affiliation: Department of Medicine, Cardiology Section, China Medical University-An Nan Hospital, Tainan, Taiwan; Department of Medicine, China Medical University, Taichung, Taiwan.
authors.forename: Tsung-Ming
authors.initials: TM
authors.lastname: Lee
authors.affiliation: Bioinnovation Center, Tzu Chi Foundation; Department of Pathology, Buddhist Tzu Chi General Hospital, Tzu Chi University.
authors.forename: Horng-Jyh
authors.initials: HJ
authors.lastname: Harn
authors.affiliation: Department of Life Science, Graduate Institute of Biotechnology, National Dong Hwa University, Hualien, Taiwan.
authors.forename: Tzyy-Wen
authors.initials: TW
authors.lastname: Chiou
authors.affiliation: Gwo Xi Stem Cell Applied Technology, Hsinchu, Taiwan; Department of Bioinformatics, Chung Hua University, Hsinchu, Taiwan.
authors.forename: Ming-Hsi
authors.initials: MH
authors.lastname: Chuang
authors.affiliation: Gwo Xi Stem Cell Applied Technology, Hsinchu, Taiwan.
authors.forename: Chun-Hung
authors.initials: CH
authors.lastname: Chen
authors.affiliation: Gwo Xi Stem Cell Applied Technology, Hsinchu, Taiwan.
authors.forename: Po-Cheng
authors.initials: PC
authors.lastname: Lin
authors.affiliation: Bioinnovation Center, Tzu Chi Foundation; Department of Neurosurgery, Buddhist Tzu Chi General Hospital, Tzu Chi University. Electronic address: shinnzong@yahoo.com.tw.
authors.forename: Shinn-Zong
authors.initials: SZ
authors.lastname: Lin
mesh_terms: D000273:Adipose Tissue / Q000166:cytology*; D053687:Adult Stem Cells / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000175:diagnosis / Q000209:etiology*; D015415:Biomarkers; D054338:Cell Transdifferentiation / Q000187:drug effects; D004452:Echocardiography; D005355:Fibrosis; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism*; D006334:Heart Function Tests; D006439:Hemodynamics; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D009203:Myocardial Infarction / Q000150:complications* / Q000175:diagnosis / Q000378:metabolism*; D009389:Neovascularization, Pathologic; D020932:Nerve Growth Factor / Q000378:metabolism*; D010641:Phenotype; D010796:Phthalic Anhydrides / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D033581:Stem Cell Transplantation
chemical_list: D015415:Biomarkers; D010796:Phthalic Anhydrides; D017382:Reactive Oxygen Species; D020932:Nerve Growth Factor; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; C026105:butylidenephthalide
keywords: Adipose-derived stem cells; Arrhythmia; Butylidenephthalide; Glycogen synthase kinase-3β; Preconditioned; Sympathetic hyperinnervation