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.
Highlights
Transient receptor potential vanilloid 4 (TRPV4) is widely expressed in the nervous system and other tissues, including the lungs, bladder and skin.[1]
These results provide in vivo evidence that the over-activation of TRPV4 may result in apoptosis in the hippocampus
TRPV4 is sensitive to various types of stimuli, including hypoosmotic stimulation, mechanical force, the metabolism of arachidonic acid (AA) and synthetic ligands
Summary
TRPV4 is widely expressed in the nervous system and other tissues, including the lungs, bladder and skin.[1]. TRPV4 can be activated by cell swelling-induced mechanical stimulation and metabolites of AA that are always associated with cerebral ischemia. The protein level of TRPV4 has been reported to increase with ongoing reperfusion in a mouse model of middle cerebral artery occlusion (MCAO).[7]. The over- or hyper-activation of TRPV4 is likely during cerebral ischemia-reperfusion. Cell apoptosis, which is one of the major causes of cerebral ischemic injury, becomes prominent after reperfusion for 24–72 h.12. It has been reported that excessive Ca2+ entry through TRPV4 leads to apoptosis in mouse retinal ganglion cells, which may be due to the activation of Ca2+-dependent pro-apoptotic signaling pathways.[13] Mitogen-activated protein kinase (MAPK) signaling pathways that are involved in cerebral ischemic injury have important roles in regulating
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