title: Activation of transient receptor potential vanilloid 4 induces apoptosis in hippocampus through downregulating PI3K/Akt and upregulating p38 MAPK signaling pathways.
abstract: Transient receptor potential vanilloid 4 (TRPV4) is a calcium-permeable cation channel that is sensitive to cell swelling, arachidonic acid and its metabolites, epoxyeicosatrienoic acids, which are associated with cerebral ischemia. The activation of TRPV4 induces cytotoxicity in many types of cells, accompanied by an increase in the intracellular free calcium concentration. TRPV4 activation modulates the mitogen-activated protein kinase (MAPK) and phosphatidyl inositol 3 kinase (PI3K)/ protein kinase B (Akt) signaling pathways that regulate cell death and survival. Herein, we examined TRPV4-induced neuronal apoptosis by intracerebroventricular (ICV) injection of a TRPV4 agonist (GSK1016790A) and assessed its involvement in cerebral ischemic injury. ICV injection of GSK1016790A dose-dependently induced apoptosis in the mouse hippocampi (GSK-injected mice). The protein level of phosphorylated p38 MAPK (p-p38 MAPK) was markedly increased and that of phosphorylated c-Jun N-terminal protein kinase (p-JNK) was virtually unchanged. TRPV4 activation also decreased Bcl-2/Bax protein ratio and increased the cleaved caspase-3 protein level, and these effects were blocked by a PI3K agonist and a p38 MAPK antagonist, but were unaffected by a JNK antagonist. ICV injection of the TRPV4 antagonist HC-067047 reduced brain infarction after reperfusion for 48 h in mice with middle cerebral artery occlusion (MCAO). In addition, HC-067047 treatment attenuated the decrease in the phosphorylated Akt protein level and the increase in p-p38 MAPK protein level at 48 h after MCAO, while the increase in p-JNK protein level remained unchanged. Finally, the decreased Bcl-2/Bax protein ratio and the increased cleaved caspase-3 protein level at 48 h after MCAO were markedly attenuated by HC-067047. We conclude that activation of TRPV4 induces apoptosis by downregulating PI3K/Akt and upregulating p38 MAPK signaling pathways, which is involved in cerebral ischemic injury.
authors.affiliation: Department of Physiology, Nanjing Medical University, Nanjing, PR China.
authors.forename: P
authors.initials: P
authors.lastname: Jie
authors.affiliation: Department of Physiology, Nanjing Medical University, Nanjing, PR China.
authors.forename: Z
authors.initials: Z
authors.lastname: Hong
authors.affiliation: Department of Physiology, Nanjing Medical University, Nanjing, PR China.
authors.forename: Y
authors.initials: Y
authors.lastname: Tian
authors.affiliation: Department of Physiology, Nanjing Medical University, Nanjing, PR China.
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Physiology, Nanjing Medical University, Nanjing, PR China.
authors.forename: L
authors.initials: L
authors.lastname: Lin
authors.affiliation: Department of Physiology, Nanjing Medical University, Nanjing, PR China.
authors.forename: L
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Research Center of Ion Channelopathy, Institute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China.
authors.forename: Y
authors.initials: Y
authors.lastname: Du
authors.affiliation: Department of Physiology, Nanjing Medical University, Nanjing, PR China.
authors.forename: L
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Physiology, Nanjing Medical University, Nanjing, PR China.
authors.forename: L
authors.initials: L
authors.lastname: Chen
mesh_terms: D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D053148:Caspase 3 / Q000378:metabolism; D015536:Down-Regulation; D004789:Enzyme Activation; D006624:Hippocampus / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000473:pathology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009025:Morpholines / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000096:biosynthesis*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D050916:TRPV Cation Channels / Q000819:agonists / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000096:biosynthesis / Q000378:metabolism*
chemical_list: D000873:Anthracenes; C573308:HC-067047; D007093:Imidazoles; D009025:Morpholines; C530602:N-(1-((4-(2-(((2,4-dichlorophenyl)sulfonyl)amino)-3-hydroxypropanoyl)-1-piperazinyl)carbonyl)-3-methylbutyl)-1-benzothiophene-2-carboxamide; D009842:Oligopeptides; D019253:Proto-Oncogene Proteins c-bcl-2; D011725:Pyridines; D011758:Pyrroles; D013449:Sulfonamides; D050916:TRPV Cation Channels; C486576:Trpv4 protein, mouse; C099158:acetyl-aspartyl-glutamyl-valyl-aspartal; D051028:bcl-2-Associated X Protein; C432165:pyrazolanthrone; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D053148:Caspase 3; D007930:Leucine; C093642:SB 203580