Inhibition of histone deacetylase 3 by MiR-494 alleviates neuronal loss and improves neurological recovery in experimental stroke.
HDAC3 is an essential negative regulator of neuronal plasticity and memory formation. Although a chemical inhibitor has been invented, little is known about its endogenous modulators. We explored whether miR-494 affects HDAC3-mediated neuronal injury following acute ischemic stroke. A substantial increase in plasma miR-494 was detected in AIS patients and was positively associated with the mRS at one year after symptom onset. The miR-494 levels were transiently increased in the infarcted brain tissue of mice. In contrast, miR-494 levels were reduced in neurons but increased in the medium after OGD. Intracerebroventricular injection of miR-494 agomir reduced neuronal apoptosis and infarct volume at the acute stage of MCAO, promoted axonal plasticity and long-term outcomes at the recovery stage, suppressed neuronal ataxin-3 and HDAC3 expression and increased acetyl-H3K9 levels in the ipsilateral hemisphere. In vitro studies confirmed that miR-494 posttranslationally inhibited HDAC3 in neurons and prevented OGD-induced neuronal axonal injury. The HDAC3 inhibitor increased acetyl-H3K9 levels and reversed miR-494 antagomir-aggravated acute cerebral ischemic injury, as well as brain atrophy and long-term functional recovery. These results suggest that miR-494 may serve as a predictive biomarker of functional outcomes in AIS patients and a potential therapeutic target for the treatment of ischemic stroke.
['Zhao|Haiping|H|', 'Li|Guangwen|G|', 'Zhang|Sijia|S|', 'Li|Fangfang|F|', 'Wang|Rongliang|R|', 'Tao|Zhen|Z|', 'Ma|Qingfeng|Q|', 'Han|Ziping|Z|', 'Yan|Feng|F|', 'Fan|Junfen|J|', 'Li|Lingzhi|L|', 'Ji|Xunming|X|', 'Luo|Yumin|Y|0000-0002-2712-8974']
D000818:Animals D000067699:Ataxin-3 D002545:Brain Ischemia D004195:Disease Models, Animal D005260:Female D015971:Gene Expression Regulation, Enzymologic D056572:Histone Deacetylase Inhibitors D006655:Histone Deacetylases D006801:Humans D008297:Male D051379:Mice D035683:MicroRNAs D009473:Neuronal Plasticity D009474:Neurons D020521:Stroke
miR-494 neuron HDAC3 Ischemic stroke