Atorvastatin inhibits neuronal apoptosis via activating cAMP/PKA/p‐CREB/BDNF pathway in hypoxic‐ischemic neonatal rats

Yu, Luting; Liu, Shixi; Zhou, Ruixi; Sun, Hao; Su, Xiaojuan; Liu, Qian; Li, Shiping; Ying, Junjie; Zhao, Fengyan; Mu, Dezhi; Qu, Yi

doi:10.1096/fj.202101654rr

Cited by 26 publications

(14 citation statements)

References 55 publications

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“…As discussed earlier we and others have demonstrated that SIRT1 activation enhances cAMP levels [12,56,57]. Perhaps surprisingly, quite a few studies had linked elevated intracellular levels of cAMP to apoptosis in various cell types [77][78][79] including ovarian follicular cells and GCs [80][81][82][83]. For instance, it was shown that treatment of GCs with forskolin, or 8-bromo-cAMP induced apoptosis as evidenced by DNA fragmentation and chromatin condensation.…”

Section: Discussionmentioning

confidence: 88%

Diverse actions of sirtuin-1 on ovulatory genes and cell death pathways in human granulosa cells

Sapuleni

Szymańska

Meidan

2022

Reprod Biol Endocrinol

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Background Human granulosa-lutein cells (hGLCs) amply express sirtuin-1 (SIRT1), a NAD + -dependent deacetylase that is associated with various cellular functions. SIRT1 was shown to elevate cAMP on its own and additively with human chorionic gonadotropin (hCG), it is therefore interesting to examine if SIRT1 affects other essential hGLC functions. Methods Primary hGLCs, obtained from the follicular aspirates of women undergoing IVF and SV40-transfected, immortalized hGLCs (SVOG cells), were used. Primary cells were treated with SIRT1 specific activator SRT2104, as well as hCG or their combination. Additionally, siRNA-targeting SIRT1 construct was used to silence endogenous SIRT1 in SVOG cells. PTGS2, EREG, VEGFA and FGF2 expression was determined using quantitative polymerase chain reaction (qPCR). Apoptotic and necroptotic proteins were determined by specific antibodies in western blotting. Cell viability/apoptosis was determined by the XTT and flow cytometry analyses. Data were analyzed using student t-test or Mann–Whitney U test or one-way ANOVA followed by Tukey HSD post hoc test. Results In primary and immortalized hGLCs, SRT2104 significantly upregulated key ovulatory and angiogenic genes: PTGS2, EREG, FGF2 and VEGFA, these effects tended to be further augmented in the presence of hCG. Additionally, SRT2104 dose and time-dependently decreased viable cell numbers. Flow cytometry of Annexin V stained cells confirmed that SIRT1 reduced live cell numbers and increased late apoptotic and necrotic cells. Moreover, we found that SIRT1 markedly reduced anti-apoptotic BCL-XL and MCL1 protein levels and increased cleaved forms of pro-apoptotic proteins caspase-3 and PARP. SIRT1 also significantly induced necroptotic proteins RIPK1 and MLKL. RIPK1 inhibitor, necrostatin-1 mitigated SIRT1 actions on RIPK1 and MLKL but also on cleaved caspase-3 and PARP and in accordance on live and apoptotic cells, implying a role for RIPK1 in SIRT1-induced cell death. SIRT1 silencing produced inverse effects on sorted cell populations, anti-apoptotic, pro-apoptotic and necroptotic proteins, corroborating SIRT1 activation. Conclusions These findings reveal that in hGLCs, SIRT1 enhances the expression of ovulatory and angiogenic genes while eventually advancing cell death pathways. Interestingly, these seemingly contradictory events may have occurred in a cAMP-dependent manner.

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Section: Discussionmentioning

confidence: 88%

Diverse actions of sirtuin-1 on ovulatory genes and cell death pathways in human granulosa cells

Sapuleni

Szymańska

Meidan

2022

Reprod Biol Endocrinol

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“…27,28 Furthermore, cognitive dysfunction caused by hypoxia/ischemia brain injury may be alleviated by activating the BDNF/TrkB signaling. 29,30 Remarkably, our experiments revealed that HPC activated the BDNF/TrkB signaling and the PLCγ pathway in the hippocampus (Figure 9) and then improved spatial cognition of mice.…”

Section: ■ Discussionmentioning

confidence: 66%

Hypoxic Preconditioning Modulates BDNF and Its Signaling through DNA Methylation to Promote Learning and Memory in Mice

Zhang

Jia

et al. 2023

ACS Chem. Neurosci.

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Hypoxic preconditioning (HPC) as an endogenous mechanism can resist hypoxia/ischemia injury and exhibit protective effects on neurological function including learning and memory. Although underlying molecular mechanisms remain unclear, HPC probably regulates the expression of protective molecules by modulating DNA methylation. Brain-derived neurotrophic factor (BDNF) activates its signaling upon binding to the tropomyosin-related kinase B (TrkB) receptor, which is involved in neuronal growth, differentiation, and synaptic plasticity. Therefore, this study focused on the mechanism by which HPC regulates BDNF and BDNF/TrkB signaling through DNA methylation to influence learning and memory. Initially, the HPC model was established by hypoxia stimulations on ICR mice. We found that HPC downregulated the expression of DNA methyltransferase (DNMT) 3A and DNMT3B. Then, the upregulation of BDNF expression in HPC mice was generated from a decrease in DNA methylation of the BDNF gene promoter detected by pyrophosphate sequencing. Subsequently, upregulation of BDNF activated BDNF/TrkB signaling and ultimately improved learning and spatial memory in HPC mice. Moreover, after mice were intracerebroventricularly injected with the DNMT inhibitor, the restraint of DNA methylation accompanied by an increase of BDNF and BDNF/TrkB signaling was also discovered. Finally, we observed that the inhibitor of BDNF/TrkB signaling prevented HPC from ameliorating learning and memory in mice. However, the DNMT inhibitor promoted spatial cognition in mice. Thus, we suggest that HPC may upregulate BDNF by inhibiting DNMTs and decreasing DNA methylation of the BDNF gene and then activate BDNF/TrkB signaling to improve learning and memory in mice. This may provide theoretical guidance for the clinical treatment of cognitive dysfunction caused by ischemia/hypoxia disease.

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“…Cerebral I/R injury results in intricate signaling pathways inducing apoptosis, a type of programmed cell death (Matei et al, 2018). In damaged brain tissue, there were multiple genes that modulate neuronal apoptosis, involving Bcl-2 (a gene that hinders apoptosis) and Bax (a gene that accelerates apoptosis) and caspase 3 (Cai et al, 2022;Yu et al, 2022). The heterodimer of Bcl-2/Bax will be formed to hinder apoptosis when the expression of Bcl-2 augmented.…”

Section: Discussionmentioning

confidence: 99%

Trilobatin attenuates cerebral ischemia/reperfusion-induced blood-brain-barrier dysfunction by targeting MMP9: The legend of a food additive

Feng

Lin

et al. 2023

Preprint

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Background and Purpose: Blood-brain barrier (BBB) breakdown is one of the most crucial pathological changes of cerebral ischemia-reperfusion (I/R) injury. Trilobatin (TLB), a naturally occurring food additive, exerts neuroprotective effect against cerebral I/R injury as demonstrated in our previous study. This study was designed to investigate the effect of TLB on disruption of BBB after cerebral I/R injury. Experimental Approach: Rats with focal cerebral ischemia caused by transient middle cerebral artery occlusion (MCAO) and brain microvascular endothelial cells along with human astrocytes to mimic blood brain barrier (BBB) injury caused by oxygen and glucose deprivation (OGD) followed by reoxygenation (OGD/R). Key results: The results showed that TLB effectively maintained the integrity of BBB and inhibited neuronal loss following cerebral I/R challenge. Furthermore, TLB dramatically increased tight junction proteins including ZO-1, occludin and claudin 5, as well as decreased the levels of apolipoprotein E (APOE) 4, cyclophilin A (CypA), and phosphorylated nuclear factor kappa B (NF-κB), thereby reduced proinflammatory cytokines. In addition, TLB also decreased Bax/Bcl-2 ratio and cleaved-caspase 3 level along with reduced the number of apoptotic neurons. Intriguingly, molecular docking and transcriptomics predicted MMP9 was a prominent gene evoked by TLB treatment. Furthermore, the protective effect of TLB on OGD/R-induced the loss of BBB integrity in human brain microvascular endothelial cell and astrocyte co-cultures in vitro was markedly reinforced by knockdown of MMP9. Conclusions and implications: Our findings reveal a novel property of TLB: saving BBB disruption following cerebral I/R via targeting MMP9 and inhibiting APOE4/CypA/NF-κB axis.

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Atorvastatin inhibits neuronal apoptosis via activating cAMP/PKA/p‐CREB/BDNF pathway in hypoxic‐ischemic neonatal rats

Cited by 26 publications

References 55 publications

Diverse actions of sirtuin-1 on ovulatory genes and cell death pathways in human granulosa cells

Diverse actions of sirtuin-1 on ovulatory genes and cell death pathways in human granulosa cells

Hypoxic Preconditioning Modulates BDNF and Its Signaling through DNA Methylation to Promote Learning and Memory in Mice

Trilobatin attenuates cerebral ischemia/reperfusion-induced blood-brain-barrier dysfunction by targeting MMP9: The legend of a food additive

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