Repression of neuronal nitric oxide (nNOS) synthesis by MTA1 is involved in oxidative stress-induced neuronal damage.
The Metastasis-associated protein 1 (MTA1) coregulator, an essential component of the nucleosome remodeling and deacetylase (NuRD) complex, potentiates neuroprotective effects against ischemia/reperfusion (I/R) injury. But the underlying mechanism(s) remain largely unknown. Here, we discovered that neuronal MTA1 was a target of oxidative stress, and stimulation of neurons with oxygen glucose deprivation (OGD) treatment significantly inhibited MTA1 expression. Additionally, MTA1 depletion augmented ischemic oxidative stress and thus promoted oxidative stress-induced neuronal cell death by OGD. While studying the impact of MTA1 status on global neuronal gene expression, we unexpectedly discovered that MTA1 may modulate OGD-induced neuronal damage via regulation of distinct nitric oxide synthase (NOS) (namely neuronal NOS, nNOS) signaling. We provided in vitro evidence that NOS1 is a chromatin target of MTA1 in OGD-insulted neurons. Mechanistically, neuronal ischemia-mediated repression of NOS1 expression is accompanied by the enhanced recruitment of MTA1 along with histone deacetylases (HDACs) to the NOS1 promoter, which could be effectively blocked by a pharmacological inhibitor of the HDACs. These findings collectively reveal a previously unrecognized, critical homeostatic role of MTA1, both as a target and as a component of the neuronal oxidative stress, in the regulation of acute neuronal responses against brain I/R damage. Our study also provides a molecular mechanistic explanation for the previously reported neurovascular protection by selective nNOS inhibitors.
Department of Anesthesiology, Honghui Hospital, Xi'an Jiaotong University College of Medicine, Xi'an 710054, China.
Zi-Jun
ZJ
Gao
Department of Ophthalmology, Xi'an No. 4 Hospital, Guangren Hospital of Xi'an Jiaotong University, Xi'an 710004, China.
Jie
J
Min
Department of Anesthesiology, Honghui Hospital, Xi'an Jiaotong University College of Medicine, Xi'an 710054, China.
Xu-Cai
XC
Wu
The 1st Cadet Brigade, Fourth Military Medical University, Xi'an 710032, China.
Tian
T
Yang
Xi'an Health Management Service Center, Xi'an 710032, China.
Chang-You
CY
Yan
Department of Anesthesiology, Honghui Hospital, Xi'an Jiaotong University College of Medicine, Xi'an 710054, China. Electronic address: dongbuhuai@126.com.
Bu-Huai
BH
Dong
Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi'an 710038, China. Electronic address: baltimore@163.com.
Tao
T
Zhang
D017209:Apoptosis / Q000235:genetics; D015153:Blotting, Western; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D005947:Glucose / Q000378:metabolism; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009474:Neurons / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013997:Time Factors; D015534:Trans-Activators
D002843:Chromatin; C089320:MTA1 protein, human; D017382:Reactive Oxygen Species; D012097:Repressor Proteins; D015534:Trans-Activators; D009569:Nitric Oxide; C496320:NOS1 protein, human; D052248:Nitric Oxide Synthase Type I; D006655:Histone Deacetylases; D005947:Glucose; D010100:Oxygen
Deacetylation; Ischemia/reperfusion (I/R); MTA1; Neuron; Neuronal nitric oxide synthase (nNOS)