Nicotinamide Mononucleotide Adenylyltransferase 1 Regulates Cerebral Ischemia-Induced Blood-Brain Barrier Disruption Through NAD + /SIRT1 Signaling Pathway.
Yang ZhangXun GuoZhifeng PengChang LiuLili RenJia LiangPeng WangPublished in: Molecular neurobiology (2022)
The molecular mechanisms of blood-brain barrier (BBB) disruption in the early stage after ischemic stroke are poorly understood. In the present study, we investigated the potential role of nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1) in ischemia-induced BBB damage using an animal middle cerebral artery occlusion (MCAO) model of ischemic stroke. Recombinant human NMNAT1 (rh-NMNAT1) was administered intranasally and Sirtuin 1 (SIRT1) siRNA was administered by intracerebroventricular injection. Our results indicate that rh-NMNAT1 reduced infarct volume, improved functional outcome, and decreased BBB permeability in mice after ischemic stroke. Furthermore, rh-NMNAT1 prevented the loss of tight junction proteins (occludin and claudin-5) and reduced cell apoptosis in ischemic microvessels. NMNAT1-mediated BBB permeability was correlated with the elevation of nicotinamide adenine dinucleotide (NAD + )/NADH ratio and SIRT1 level in brain microvascular endothelial cells. In addition, rh-NMNAT1 treatment significantly decreased the levels of acetylated nuclear factor-κB, acetylated p53, and matrix metalloproteinase-9 in ischemic microvessels. Moreover, the protective effects of rh-NMNAT1 could be reversed by SIRT1 siRNA. In conclusion, these findings indicate that rh-NMNAT1 protects BBB integrity after cerebral ischemia via the NAD + /SIRT1 signaling pathway in brain microvascular endothelial cells. NMNAT1 may be a novel potential therapeutic target for reducing BBB disruption after ischemic stroke.
Keyphrases
- blood brain barrier
- cerebral ischemia
- endothelial cells
- high glucose
- signaling pathway
- oxidative stress
- early stage
- ischemia reperfusion injury
- middle cerebral artery
- atrial fibrillation
- nuclear factor
- epithelial mesenchymal transition
- toll like receptor
- recombinant human
- subarachnoid hemorrhage
- heart failure
- adipose tissue
- drug induced
- white matter
- type diabetes
- multiple sclerosis
- resting state
- skeletal muscle
- acute coronary syndrome
- vascular endothelial growth factor
- neoadjuvant chemotherapy
- sentinel lymph node
- human health