Sirt3 Protects Against Ischemic Stroke Injury by Regulating HIF-1α/VEGF Signaling and Blood-Brain Barrier Integrity.
Xiao YangYanshuang ZhangKeyi GengKe YangJiaxiang ShaoWei-Liang XiaPublished in: Cellular and molecular neurobiology (2020)
Sirtuin 3 (Sirt3) is a member of the Sirtuin family proteins and known to regulate multiple physiological processes such as metabolism and aging. As stroke is an aging-related disease, in this work, we attempt to examine the role and potential mechanism of Sirt3 in regulating ischemic stroke by using a permanent middle cerebral artery occlusion (pMCAO) model in wild type (WT) and Sirt3 knockout (KO) mice, coupled with oxygen glucose deprivation (OGD) experiments in cultured primary astrocytes. Sirt3 deficiency aggravated neuronal cell apoptosis and neurological deficits after brain ischemia. In addition, Sirt3 KO mice showed more severe blood-brain barrier (BBB) disruption and inflammatory responses compared with WT group in the acute phase. Furthermore, specific overexpression of Sirt3 in astrocytes by injecting glial fibrillary acidic protein (GFAP)::Sirt3 virus in ischemic region showed protective effect against stroke-induced damage. Mechanistically, Sirt3 could regulate vascular endothelial growth factor (VEGF) expression by inhibiting hypoxia inducible factor-1α (HIF-1α) signaling after ischemia (OGD). Our results have shown that Sirt3 plays a protective role in ischemic stroke via regulating HIF-1α/VEGF signaling in astrocytes, and reversal of the Sirt3 expression at the acute phase could be a worthy direction for stroke therapy.
Keyphrases
- blood brain barrier
- oxidative stress
- ischemia reperfusion injury
- vascular endothelial growth factor
- cerebral ischemia
- endothelial cells
- atrial fibrillation
- middle cerebral artery
- cell proliferation
- poor prognosis
- type diabetes
- traumatic brain injury
- high glucose
- multiple sclerosis
- small molecule
- diabetic rats
- stem cells
- binding protein
- transcription factor
- blood pressure
- spinal cord injury
- brain injury
- cell therapy
- protein protein
- stress induced