title: Sodium orthovanadate suppresses palmitate-induced cardiomyocyte apoptosis by regulation of the JAK2/STAT3 signaling pathway.
abstract: Elevated circulatory free fatty acids (FFAs) especially saturated FFAs, such as palmitate (PA), are detrimental to the heart. However, mechanisms responsible for this phenomenon remain unknown. Here, the role of JAK2/STAT3 in PA-induced cytotoxicity was investigated in cardiomyocytes. We demonstrate that PA suppressed the JAK2/STAT3 pathway by dephosphorylation of JAK2 (Y1007/1008) and STAT3 (Y705), and thus blocked the translocation of STAT3 into the nucleus. Conversely, phosphorylation of S727, another phosphorylated site of STAT3, was increased in response to PA treatment. Pretreatment of JNK inhibitor, but not p38 MAPK inhibitor, inhibited STAT3 (S727) activation induced by PA and rescued the phosphorylation of STAT3 (Y705). The data suggested that JNK may be another upstream factor regulating STAT3, and verified the important function of P-STAT3 (Y705) in PA-induced cardiomyocyte apoptosis. Sodium orthovanadate (SOV), a protein tyrosine phosphatase inhibitor, obviously inhibited PA-induced apoptosis by restoring JAK2/STAT3 pathways. This effect was diminished by STAT3 inhibitor Stattic. Collectively, our data suggested a novel mechanism that the inhibition of JAK2/STAT3 activation was responsible for palmitic lipotoxicity and SOV may act as a potential therapeutic agent by targeting JAK2/STAT3 in lipotoxic cardiomyopathy treatment.
authors.affiliation: Institute of Developmental Biology, School of Life Science, Shandong University, Jinan, 250100, People's Republic of China.
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.affiliation: Institute of Developmental Biology, School of Life Science, Shandong University, Jinan, 250100, People's Republic of China.
authors.forename: Hui
authors.initials: H
authors.lastname: Fu
authors.affiliation: Institute of Developmental Biology, School of Life Science, Shandong University, Jinan, 250100, People's Republic of China.
authors.forename: Fen
authors.initials: F
authors.lastname: Chang
authors.affiliation: Institute of Developmental Biology, School of Life Science, Shandong University, Jinan, 250100, People's Republic of China.
authors.forename: Jinlan
authors.initials: J
authors.lastname: Wang
authors.affiliation: Institute of Developmental Biology, School of Life Science, Shandong University, Jinan, 250100, People's Republic of China.
authors.forename: Shangli
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Internal Medicine, College of Medicine, East Tennessee State University, Johnson City, TN, 37614, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Caudle
authors.affiliation: Institute of Developmental Biology, School of Life Science, Shandong University, Jinan, 250100, People's Republic of China. jingzhao@sdu.edu.cn.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.affiliation: School of Pharmacy, Central South University, Changsha, 410023, People's Republic of China. yin@etsu.edu.|Department of Internal Medicine, College of Medicine, East Tennessee State University, Johnson City, TN, 37614, USA. yin@etsu.edu.
authors.forename: Deling
authors.initials: D
authors.lastname: Yin
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D010168:Palmitates / Q000037:antagonists & inhibitors / Q000633:toxicity*; D010766:Phosphorylation / Q000187:drug effects; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors; D017207:Rats, Sprague-Dawley; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014638:Vanadates / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D010168:Palmitates; D050796:STAT3 Transcription Factor; D014638:Vanadates; D053614:Janus Kinase 2; D017027:Protein Tyrosine Phosphatases
keywords: Apoptosis; Cardiomyocyte; JAK2; Palmitate; STAT3; Sodium orthovanadate