ArticleThe European journal of neuroscience2019
Inhibition of calcium/calmodulin-dependent protein kinase kinase (CaMKK) exacerbates impairment of endothelial cell and blood-brain barrier after stroke.
Article in The European journal of neuroscience, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 40 citations in OpenAlex.
- Serum Amyloid A-Dependent Inflammasome Activation and Acute Injury in a Mouse Model of Experimental Stroke.International journal of molecular sciences · 2026Article
- Single-cell RNA sequencing reveals disease associated changes in brain endothelial cells in the 5XFAD mouse.Fluids and barriers of the CNS · 2026Article
- CaMKKβ regulates transcription factor Elf2 gene methylation to maintain endothelial junctional barrier integrity.iScience · 2026Article
- Single-cell transcriptomic analysis reveals age-related remodeling of brain endothelial cells.Aging brain · 2026Article
- LRRC8A in endothelial cells contributes to the aberrant blood-brain barrier integrity in ischaemic stroke.Stroke and vascular neurology · 2025Article
- Genetic deletion of microRNA-15a/16-1 in pericytes stimulates cerebral angiogenesis and promotes functional recovery after ischemic stroke.Angiogenesis · 2025Article
- Understanding the Blood-Brain Barrier: From Physiology to Pathology.Advances in experimental medicine and biology · 2025Review
- From Microcirculation to Aging-Related Diseases: A Focus on Endothelial SIRT1.Pharmaceuticals (Basel, Switzerland) · 2024Review
- Proteome profiling of hippocampus reveals the neuroprotective effect of mild hypothermia on global cerebral ischemia-reperfusion injury in rats.Scientific reports · 2023Article
- A comprehensive review on the impact of calcium and vitamin D insufficiency and allied metabolic disorders in females.Food science & nutrition · 2023Review
- Sirtuins: Promising Therapeutic Targets to Treat Ischemic Stroke.Biomolecules · 2023Review
- Atomoxetine and Fluoxetine Activate AMPK-ACC-CPT1 Pathway in Human SH-SY5Y and U-87 MG Cells.Psychiatry investigation · 2023Article
- Myeloid-derived MIF drives RIPK1-mediated cerebromicrovascular endothelial cell death to exacerbate ischemic brain injury.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- SGC-CAMKK2-1: A Chemical Probe for CAMKK2.Cells · 2023Article
- Molecular Mechanisms Underlying CaInternational journal of molecular sciences · 2022Review
- A novel link between silent information regulator 1 and autophagy in cerebral ischemia-reperfusion.Frontiers in neuroscience · 2022Review
- Anti-Inflammatory Effects of Natural Products on Cerebral Ischemia.Frontiers in pharmacology · 2022Review
- Salvianolic Acid C Protects against Cisplatin-Induced Acute Kidney Injury through Attenuation of Inflammation, Oxidative Stress and Apoptotic Effects and Activation of the CaMKK-AMPK-Sirt1-Associated Signaling Pathway in Mouse Models.Antioxidants (Basel, Switzerland) · 2021Article
- Blood-Brain Barrier Overview: Structural and Functional Correlation.Neural plasticity · 2021Review
- Activation of TGR5 protects blood brain barrier via the BRCA1/Sirt1 pathway after middle cerebral artery occlusion in rats.Journal of biomedical science · 2020Article
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Authors and funding
10 authors at 1 institution in 1 country.
Funding
Abstract
Brain microvascular endothelial cells play an essential role in maintaining blood-brain barrier (BBB) integrity, and disruption of the BBB aggravates the ischemic injury. CaMKK (α and β) is a major kinase activated by elevated intracellular calcium. Previously, we demonstrated that inhibition of CaMKK exacerbated outcomes, conversely, overexpression reduced brain injury after stroke in mice. Interestingly, CaMKK has been shown to activate a key endothelial protector, sirtuin 1 (SIRT1). We hypothesized that CaMKK protects brain endothelial cells via SIRT1 activation after stroke. In this study, Oxygen-Glucose Deprivation (OGD) was performed in human brain microvascular endothelial cells. Stroke was induced by middle cerebral artery occlusion (MCAO) in male mice. Knockdown of CaMKK β using siRNA increased cell death following OGD. Inhibition of CaMKK β by STO-609 significantly and selectively down-regulated levels of phosphorylated SIRT1 after OGD. Changes in the downstream targets of SIRT1 were observed following STO-609 treatment. The effect of STO-609 on cell viability after OGD was absent, when SIRT1 was concurrently inhibited. We also demonstrated that STO-609 increased endothelial expression of the pro-inflammatory proteins ICAM-1 and VCAM-1 and inhibition of CaMKK exacerbated OGD-induced leukocyte-endothelial adhesion. Finally, intracerebroventricular injection of STO-609 exacerbated endothelial apoptosis and reduced BBB integrity after 24-hr reperfusion following MCAO in vivo. Collectively, these results demonstrated that CaMKK inhibition reduced endothelial cell viability, exacerbated inflammatory responses and aggravated BBB impairment after ischemia. CaMKK activation may attenuate ischemic brain injury via protection of the microvascular system and a reduction in the infiltration of pro-inflammatory factors.
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