Neural JNK3 regulates blood flow recovery after hindlimb ischemia in mice via an Egr1/Creb1 axis

Kant, Shashi; Craige, Siobhan M.; Chen, Kai; Reif, Michaella M.; Learnard, Heather; Kelly, Mark; Caliz, Amada D.; Tran, Khanh‐Van; Ramo, Kasmir; Peters, Owen M.; Freeman, Marc; Davis, Roger J.; Keaney, John F.

doi:10.1038/s41467-019-11982-4

Cited by 26 publications

(14 citation statements)

References 69 publications

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“…The results showed that there is significant induction of p-Akt1 (S473), p-Akt-Pan (S472, S473, S474), p-CREB (S133), p-ERK1 (T202/Y204), p-ERK2 (T185/Y187), and p-GSK3α/β (S21/S9) expression in rA2 treated HBMEC ( Figure 3A ). CREB is the transcription factor that regulates vascular remodeling via mediating downstream growth factors, including VEGF ( Kant et al, 2019 ). To analyze whether rA2 treatment induces the protein levels of p-CREB, VEGF, and BDNF in HBMEC, western blotting analysis was used.…”

Section: Resultsmentioning

confidence: 99%

Recombinant Annexin A2 Administration Improves Neurological Outcomes After Traumatic Brain Injury in Mice

et al. 2021

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Microvascular failure is one of the key pathogenic factors in the dynamic pathological evolution after traumatic brain injury (TBI). Our laboratory and others previously reported that Annexin A2 functions in blood-brain barrier (BBB) development and cerebral angiogenesis, and recombinant human Annexin A2 (rA2) protected against hypoxia plus IL-1β-induced cerebral trans-endothelial permeability in vitro, and cerebral angiogenesis impairment of AXNA2 knock-out mice in vivo. We thereby hypothesized that ANXA2 might be a cerebrovascular therapy candidate that targets early BBB integrity disruption, and subacute/delayed cerebrovascular remodeling after TBI, ultimately improve neurological outcomes. In a controlled cortex impact (CCI) mice model, we found rA2 treatment (1 mg/kg) significantly reduced early BBB disruption at 24 h after TBI; and rA2 daily treatment for 7 days augmented TBI-induced mRNA levels of pro-angiogenic and endothelial-derived trophic factors in cerebral microvessels. In cultured human brain microvascular endothelial cells (HBMEC), through MAPKs array, we identified that rA2 significantly activated Akt, ERK, and CREB, and the activated CREB might be responsible for the rA2-induced VEGF and BDNF expression. Moreover, rA2 administration significantly increased cerebral angiogenesis examined at 14 days and vessel density at 28 days after TBI in mice. Consistently, our results validated that rA2 significantly induced angiogenesis in vitro, evidenced by tube formation and scratched migration assays in HBMEC. Lastly, we demonstrated that rA2 improved long-term sensorimotor and cognitive function, and reduced brain tissue loss at 28 days after TBI. Our findings suggest that rA2 might be a novel vascular targeting approach for treating TBI.

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Section: Resultsmentioning

confidence: 99%

Recombinant Annexin A2 Administration Improves Neurological Outcomes After Traumatic Brain Injury in Mice

et al. 2021

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“…Creb1 could bind to Egr1 promoters [ 27 ]. As a member of the bZIP superfamily, the cAMP response element-binding protein 1 (Creb1) was observed improving interaction with Erg1 after hypoxia [ 42 ]. Creb1 and Egr1 exhibited a synergistic role in governing MAO-B gene expression under basal and dopamine-induced conditions [ 43 ].…”

Section: Discussionmentioning

confidence: 99%

Systematical Identification of the Protective Effect of Danhong Injection and BuChang NaoXinTong Capsules on Transcription Factors in Cerebral Ischemia Mice Brain

Wang

Guo

et al. 2020

Oxidative Medicine and Cellular Longevity

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Cerebral ischemia has led to a high rate of both disability and mortality with massive healthcare costs. Although transcriptional regulation is typically mediated by different combinations of TFs, a combined regulatory unit to synergistically activate transcription has remained unclear in cerebral ischemia, especially in different drug treatments. In this study, TFs alterations after 6 h cerebral ischemic injury and repair were performed by a concatenated tandem array of consensus transcription factor response elements (catTFREs), and vital TFs were obtained by TFs-target imbalanced network. Drug intervention used Danhong injection (DHI) and BNC (BuChang NaoXinTong Capsules), which has been widely prescribed in Chinese herb medicine for the treatment of cerebrovascular and cardiovascular diseases. There were 198 TFs identified after 6 h MCAO operation, and six TFs (Sox2, Smad3, FoxO1, Creb1, Egr,1 and Smad4) were considered as critical TFs in response to cerebral ischemia. Moreover, Smad3 was identified as a hub TF among six vital TFs, and the transcription activity of Smad3 was further verified. These 6 TFs were all reversed by DHI or BNC, indicating different medications may regulate different transcription factors through TF synergy. Moreover, validation results indicated that Smad3 was a putative target TF for DHI and BNC-mediated protection against cerebral ischemia. The observations of the present study provide a fresh understanding of biomolecules and possible new avenues for therapeutic interventions, in addition to the new intervention pattern for different treatments for ischemia stroke.

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“…In addition, JNK signaling pathway has been shown to play critical roles in regulating cell fate, being implicated in a multitude of diseases ranging from cancer to ischemic immunological/inflammatory conditions . JNKs cause changes to gene transcription, resulting in biological responses such as inflammation and/or apoptosis . Many effects of JNKs are mediated by transcription factors of the activator protein‐1 family, of which c‐Jun is the most commonly known.…”

Section: Discussionmentioning

confidence: 99%

PDRPS7 protects cardiac cells from hypoxia/reoxygenation injury through inactivation of JNKs

et al. 2020

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Myocardial ischemia/reperfusion (I/R) injury is a major complication of reperfusion therapy in myocardial infarction. Ischemic myocardium produces a variety of peptides. We recently identified PDRPS7 as a novel peptide in cardiomyocytes that can be induced by hypoxia. However, the role of PDRPS7 is unknown. Here, we investigated the effects of PDRPS7 on hypoxia/reoxygenation (H/R)‐induced injury in rat cardiomyoblast H9c2 cells and NRCMs. We found that PDRPS7 improved cell survival and attenuated lactate dehydrogenase leakage following H/R in H9c2 cells and NRCMs. PDRPS7 also alleviated H/R‐induced pulsation reduction in NRCMs. Moreover, H/R‐induced cell apoptosis was decreased in the presence of PDRPS7. H/R‐induced reactive oxygen species generation was reduced by PDRPS7; in addition, PDRPS7 did not impact H2O2‐induced cell injury. Signaling analysis demonstrated that H/R increased the phosphorylation levels of JNKs, ERKs, and p38 mitogen‐activated protein kinases. However, PDRPS7 only attenuated H/R‐induced JNK phosphorylation, but not phosphorylation of ERKs and p38. PDRPS7 protected cardiomyocytes from apoptosis by inhibiting JNK phosphorylation and c‐Jun phosphorylation pathways, markedly upregulating anti‐apoptotic Bcl‐2 expression and inhibiting that of pro‐apoptotic Bax and cleaved caspase‐3. Importantly, pharmacological activation of JNKs diminished the protective effect of PDRPS7 in terms of cell survival against H/R stimulation. In summary, our study identified PDRPS7 as a novel cardioprotective peptide against H/R challenge and this action was mediated, at least in part, through inactivation of JNKs.

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Neural JNK3 regulates blood flow recovery after hindlimb ischemia in mice via an Egr1/Creb1 axis

Cited by 26 publications

References 69 publications

Recombinant Annexin A2 Administration Improves Neurological Outcomes After Traumatic Brain Injury in Mice

Recombinant Annexin A2 Administration Improves Neurological Outcomes After Traumatic Brain Injury in Mice

Systematical Identification of the Protective Effect of Danhong Injection and BuChang NaoXinTong Capsules on Transcription Factors in Cerebral Ischemia Mice Brain

PDRPS7 protects cardiac cells from hypoxia/reoxygenation injury through inactivation of JNKs

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