Emerging Roles of Sirtuins in Ischemic Stroke
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REVIEW
Emerging Roles of Sirtuins in Ischemic Stroke David T. She 1,2 & Dong-Gyu Jo 3 & Thiruma V. Arumugam 1,2,3
Received: 22 February 2017 / Revised: 2 June 2017 / Accepted: 6 June 2017 # Springer Science+Business Media, LLC 2017
Abstract Ischemic stroke is one of the leading causes of death worldwide. It is characterized by a sudden disruption of blood flow to the brain causing cell death and damage, which will lead to neurological impairments. In the current state, only one drug is approved to be used in clinical setting and new therapies that confer ischemic neuroprotection are desperately needed. Several targets and pathways have been indicated to be neuroprotective in ischemic stroke, among which the sirtuin family of nicotinamide adenine dinucleotide (NAD+)-dependent deacetylases has emerged as important modulators of several processes in the normal physiology and pathological conditions such as stroke. Recent studies have identified some members of the sirtuin family are able to ameliorate the devastating consequences of ischemic stroke by conferring neuroprotection by means of reducing neuronal cell death, oxidative stress, and neuroinflammation whereas some sirtuins are found to be detrimental in the pathophysiology of ischemic stroke. This review summarizes implications of sirtuins in ischemic stroke and the experimental evidences that demonstrate the potential of sirtuin modulators as neuroprotective therapy for ischemic stroke.
* Thiruma V. Arumugam [email protected] 1
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
2
Neurobiology/Ageing Programme, Life Sciences Institute, National University of Singapore, Singapore 117456, Singapore
3
School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea
Keywords Sirtuins . Ischemic stroke . Cell death . Neuroprotection . Inflammation
Introduction Sirtuins (SIRTs), or silent information regulator two-like proteins, are mammalian ortholog of silent information regulator 2 (Sir2) protein in the budding yeast Saccharomyces cerevisiae [1]. The yeast SIR2 gene plays a transcriptional silencing role in heterochromatin regions (area which genes are mostly silenced), including the ribosomal gene cluster (ribosomal DNA (rDNA)), telomeres, and the hidden mating type loci HML/HMR [2]. Sir2 protein is a NAD+-dependent enzyme called histone deacetylase (HDAC) class III, which uses NAD+ as a cofactor to remove an acetyl group from the epsilon amine of lysine on a histone protein, allowing histones to wrap the DNA more tightly [3]. Subsequent studies discovered homologs of Sir2 in prokaryotes and in all eukaryotes including mammals [2], establishing a family of highly conserved enzymes known as sirtuins. Sirtuins have received widespread attention, and they have been well accepted not just as energy sensors but also as transcriptional effectors by regulating the acetylation state of many histones and nonhistone targets, thereby controlling their activities. Modulation of sirtui
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