Repression of neuronal nitric oxide (nNOS) synthesis by MTA1 is involved in oxidative stress-induced neuronal damage

Sep 8, 2016Biochemical and biophysical research communications

MTA1 reduces nerve cell nitric oxide production linked to damage from oxidative stress

AI simplified

Abstract

Stimulation of neurons with oxygen glucose deprivation significantly inhibited MTA1 expression.

MTA1 is targeted by oxidative stress, which may have implications for neuronal survival during ischemic conditions.
Depletion of MTA1 appears to increase ischemic oxidative stress, leading to higher rates of neuronal cell death.
MTA1 may influence neuronal damage from oxygen glucose deprivation by regulating neuronal nitric oxide synthase (nNOS) signaling.
MTA1 has been identified as a chromatin target of nNOS in neurons exposed to oxidative stress.
The repression of nNOS expression during neuronal ischemia correlates with increased recruitment of MTA1 and histone deacetylases to the nNOS promoter.

AI simplified

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.

Full Text

Full text is available at the source.

View full text ↗View full text (XML) ↗

Abstract

Full Text

what lands in your inbox each week: