SIRT1 mediates hypoxic preconditioning induced attenuation of neurovascular dysfunction following subarachnoid hemorrhage

Vellimana, Ananth K.; Aum, Diane J.; Diwan, Deepti; Clarke, Julian V.; Nelson, James W.; Lawrence, Molly; Han, Byung Hee; Gidday, Jeffrey M.; Zipfel, Gregory J.

doi:10.1016/j.expneurol.2020.113484

Cited by 32 publications

(29 citation statements)

References 45 publications

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“…reported that SIRT1 inhibition blocked the protective effects of hypoxic preconditioning on vasospasm and neurological deficits after SAH. In contrast, SIRT1 activation by resveratrol pretreatment abrogated vasospasm and attenuated neurological deficits following SAH ( 19 , 20 ). Another two previous studies observed that SIRT1 inhibition by sirtinol aggravated brain edema, oxidative damage, neuroinflammation, and neuronal apoptosis after SAH ( 13 , 21 ).…”

Section: Introductionmentioning

confidence: 94%

SIRT1 Promotes M2 Microglia Polarization via Reducing ROS-Mediated NLRP3 Inflammasome Signaling After Subarachnoid Hemorrhage

et al. 2021

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Mounting evidence has suggested that modulating microglia polarization from pro-inflammatory M1 phenotype to anti-inflammatory M2 state might be a potential therapeutic approach in the treatment of subarachnoid hemorrhage (SAH) injury. Our previous study has indicated that sirtuin 1 (SIRT1) could ameliorate early brain injury (EBI) in SAH by reducing oxidative damage and neuroinflammation. However, the effects of SIRT1 on microglial polarization and the underlying molecular mechanisms after SAH have not been fully illustrated. In the present study, we first observed that EX527, a potent selective SIRT1 inhibitor, enhanced microglial M1 polarization and nod-like receptor pyrin domain-containing 3 (NLRP3) inflammasome activation in microglia after SAH. Administration of SRT1720, an agonist of SIRT1, significantly enhanced SIRT1 expression, improved functional recovery, and ameliorated brain edema and neuronal death after SAH. Moreover, SRT1720 modulated the microglia polarization shift from the M1 phenotype and skewed toward the M2 phenotype. Additionally, SRT1720 significantly decreased acetylation of forkhead box protein O1, inhibited the overproduction of reactive oxygen species (ROS) and suppressed NLRP3 inflammasome signaling. In contrast, EX527 abated the upregulation of SIRT1 and reversed the inhibitory effects of SRT1720 on ROS-NLRP3 inflammasome activation and EBI. Similarly, in vitro, SRT1720 suppressed inflammatory response, oxidative damage, and neuronal degeneration, and improved cell viability in neurons and microglia co-culture system. These effects were associated with the suppression of ROS-NLRP3 inflammasome and stimulation of SIRT1 signaling, which could be abated by EX527. Altogether, these findings indicate that SRT1720, an SIRT1 agonist, can ameliorate EBI after SAH by shifting the microglial phenotype toward M2 via modulation of ROS-mediated NLRP3 inflammasome signaling.

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Section: Introductionmentioning

confidence: 94%

SIRT1 Promotes M2 Microglia Polarization via Reducing ROS-Mediated NLRP3 Inflammasome Signaling After Subarachnoid Hemorrhage

et al. 2021

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“…Several studies have implicated a protective role of SIRT1 against various neurological disorders including cerebral ischemia [32,33]. With respect to SAH-induced brain injury, SIRT1 has been linked to two of the most important forms of post-ictal secondary brain injury: EBI [34][35][36] and DCI [22]. In the case of anesthetic conditioning, there is a growing body of preclinical and clinical evidence indicating a strong protective effect of inhalational anesthetics against SAH-induced DCI [15,[37][38][39][40].…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…SIRT1 (silent mating type information regulation 2 homolog), a known nicotinamide adenine dinucleotide (NAD)-dependent deacetylase, is present ubiquitously in the brain [16,17], and several studies have demonstrated a protective role of SIRT1 in various neurological disorders [18][19][20] including SAH [21,22]. Recently, Vellimana et al [22] provided critical evidence showing that SIRT1 is a key mediator of hypoxic conditioning-induced protection against SAH-induced DCI. SIRT1 is a well-known regulator of numerous molecular pathways, several of which have been linked to the pathophysiology of DCI including endothelial nitric oxide synthase (eNOS) [23], hypoxia inducible factor 1α (HIF-1α) [24], and others [25][26][27][28].…”

Section: Introductionmentioning

confidence: 99%

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Role of SIRT1 in Isoflurane Conditioning-Induced Neurovascular Protection against Delayed Cerebral Ischemia Secondary to Subarachnoid Hemorrhage

Liu

Jayaraman

Giri

et al. 2021

IJMS

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We recently reported that isoflurane conditioning provided multifaceted protection against subarachnoid hemorrhage (SAH)-induced delayed cerebral ischemia (DCI), and this protection was through the upregulation of endothelial nitric oxide synthase (eNOS). SIRT1, an NAD-dependent deacetylase, was shown to be one of the critical regulators of eNOS. The aim of our current study is to examine the role of SIRT1 in isoflurane conditioning-induced neurovascular protection against SAH-induced DCI. Mice were divided into four groups: sham, SAH, or SAH with isoflurane conditioning (with and without EX-527). Experimental SAH via endovascular perforation was performed. Anesthetic conditioning was performed with isoflurane 2% for 1 h, 1 h after SAH. EX-527, a selective SIRT1 inhibitor, 10 mg/kg was injected intraperitoneally immediately after SAH in the EX-527 group. SIRT1 mRNA expression and activity levels were measured. Vasospasm, microvessel thrombosis, and neurological outcome were assessed. SIRT1 mRNA expression was downregulated, and no difference in SIRT1 activity was noted after isoflurane exposure. Isoflurane conditioning with and without EX-527 attenuated vasospasm, microvessel thrombosis and improved neurological outcomes. Our data validate our previous findings that isoflurane conditioning provides strong protection against both the macro and micro vascular deficits induced by SAH, but this protection is likely not mediated through the SIRT1 pathway.

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“…Silent information regulator 1 (SIRT1), an NAD + -dependent protein deacetylase, is involved in a variety of disease processes, such as inflammation, cell death and metabolism, by regulating targets via deacetylation ( 12 ). Evidence has shown that SIRT1 exerts a neuroprotective effect following ICH ( 13 ). SIRT1 protects against ICH-induced brain damage via inhibiting neuroinflammation by deacetylating NF-κB/p65( 14 ).…”

Section: Introductionmentioning

confidence: 99%

Effects and mechanisms of CTRP3 overexpression in secondary brain injury following intracerebral hemorrhage in rats

et al. 2021

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SIRT1 mediates hypoxic preconditioning induced attenuation of neurovascular dysfunction following subarachnoid hemorrhage

Cited by 32 publications

References 45 publications

SIRT1 Promotes M2 Microglia Polarization via Reducing ROS-Mediated NLRP3 Inflammasome Signaling After Subarachnoid Hemorrhage

SIRT1 Promotes M2 Microglia Polarization via Reducing ROS-Mediated NLRP3 Inflammasome Signaling After Subarachnoid Hemorrhage

Role of SIRT1 in Isoflurane Conditioning-Induced Neurovascular Protection against Delayed Cerebral Ischemia Secondary to Subarachnoid Hemorrhage

Effects and mechanisms of CTRP3 overexpression in secondary brain injury following intracerebral hemorrhage in rats

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