The role of death-associated protein kinase (DAPK) in endothelial apoptosis under fluid shear stress

Rennier, Keith; Ji, Julie Y.

doi:10.1016/j.lfs.2013.06.011

Cited by 13 publications

(8 citation statements)

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“…The death‐associated protein kinase (DAPK) family is one of the important families of STKs that regulate several biological functions in the human cells. A few research groups have reviewed DAPK1‐related subjects mostly focusing on the structure, regulation, and biological roles . In this review, our objective is to give an updated comprehensive overview about the structure, regulation, and biological roles of DAPKs and provide, for the first time, a comprehensive review on the strategies used to modulate the activity of this kinase family with small molecules from a medicinal chemistry perspective and evaluate their therapeutic outcomes.…”

Section: Introductionmentioning

confidence: 99%

Death‐associated protein kinase (DAPK) family modulators: Current and future therapeutic outcomes

Farag

Roh

2018

Medicinal Research Reviews

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Serine/threonine kinases (STKs) represent the majority of discovered kinases to date even though a few Food and Drug Administration approved STKs inhibitors are reported. The third millennium came with the discovery of an important group of STKs that reshaped our understanding of several biological signaling pathways. This family was named death-associated protein kinase family (DAPK family). DAPKs comprise five members (DAPK1, DAPK2, DAPK3, DRAK1, and DRAK2) and belong to the calcium/calmodulin-dependent kinases domain. As time goes on, the list of biological functions of this family is constantly updated. The most extensively studied member is DAPK1 (based on the publications number and Protein Data Bank reported crystal structures) that plays fundamental biological roles depending on the cellular context. DAPK1 regulates apoptosis, autophagy, contributes to the pathogenesis of Alzheimer's disease, acts as a tumor suppressor, inhibits metastasis, mediates the body responses to viral infections, and regulates the synaptic plasticity and depression. For their biological roles, several DAPKs' modulators have been reported for treatment of many diseases as well as acting as probe compounds to facilitate the understanding of the biological functions elicited by this family. Despite that, the number of reported modulators is still limited and more research needs to be conducted on the discovery of novel strategies to activate or inhibit this family. In this report, we aim at drawing more attention to this family by reviewing the recent updates regarding the structure, biological roles, and regulation of this family. In addition, the small-molecule modulators of this family are reviewed in details with their potential therapeutic outcomes evaluated to help medicinal chemists develop more potent and selective possible drug candidates.

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Section: Introductionmentioning

confidence: 99%

Death‐associated protein kinase (DAPK) family modulators: Current and future therapeutic outcomes

Farag

Roh

2018

Medicinal Research Reviews

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“… 18 On the other hand, DAPK has also been reported to exert antiapoptotic functions in different situations, as it was shown to suppress TNF α-induced apoptosis by shear stress in endothelial cells. 19 Lai and Chen 20 demonstrated that DAPK negatively regulates T-cell activation by selective inhibition in T-cell receptor-triggered NF-κB activation. 21 Furthermore, in an acute T-cell leukaemia cell line, silencing of DAPK resulted in reduced susceptibility to Fas-induced apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Altered gene expression in T-cell receptor signalling in peripheral blood leucocytes in acute coronary syndrome predicts secondary coronary events

et al. 2016

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ObjectiveComprehensive profiling of gene expression in peripheral blood leucocytes (PBLs) in patients with acute coronary syndrome (ACS) as a prognosticator is needed. We explored the specific profile of gene expression in PBLs in ACS for long-term risk stratification.Methods30 patients with ACS who underwent primary percutaneous coronary intervention (PCI) and 15 age-matched adults who participated in medical check-ups were enrolled from three centres. Peripheral blood samples were collected to extract RNA for microarray analyses.ResultsDuring the 5-year follow-up, 36% of this cohort developed the expected non-fatal coronary events (NFEs) of target lesion revascularisation (TLR) and PCI for a de novo lesion. Class comparison analysis (p<0.005) demonstrated that 83 genes among 7785 prefiltered genes (41 upregulated vs 42 downregulated genes) were extracted to classify the patients according to the occurrence of NFE. Pathway analysis based on gene ontology revealed that the NFEs were associated with altered gene expression regarding the T-cell receptor signalling pathway in ACS. Univariate t test showed that the expression level of death-associated protein kinase1 (DAPK1), known to regulate inflammation, was the most significantly negatively regulated gene in the event group (0.61-fold, p<0.0005). Kaplan-Meier curve analysis and multivariate analysis adjusted for baseline characteristics or clinical biomarkers demonstrated that lower DAPK1 expression in PBL emerged as an independent risk factor for the NFEs (HR: 8.73; CI 1.05 to 72.8, p=0.045).ConclusionsAltered gene expression in T-cell receptor signalling in PBL in ACS could be a prognosticator for secondary coronary events.Trial registration numberUMIN000001932; Results.

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“…ERK is upstream of DAPK activation via phosphorylation at Ser735 [ 43 ], phospho-p38 is an apoptotic binding partner of DAPK [ 44 ]; and JNK is downstream of DAPK via PKD regulation [ 45 ]. As we have discussed before [ 46 ], DAPK is involved in multiple apoptotic pathways including cytokine (TNFα), oxidative stress (H 2 O 2 ), or serum depletion. Our data support the theory that shear stress may target DAPK as a converging point to exert its effects of suppressing endothelial apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Shear stress attenuates apoptosis due to TNFα, oxidative stress, and serum depletion via death-associated protein kinase (DAPK) expression

Rennier

2015

BMC Res Notes

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BackgroundMisdirected apoptosis in endothelial cells participates in the development of pathological conditions such as atherosclerosis. Tight regulation of apoptosis is necessary to ensure normal cell function. The rate of cell turnover is increased at sites prone to lesion development. Laminar shear stress is protective against atherosclerosis, and helps suppress apoptosis induced by cytokines, oxidative stress, and serum depletion. Current Studies have shown that the pro-apoptotic DAPK expression and function to be regulated in part by shear stress, and that shearing cells already treated with cytokine tumor necrosis factor (TNF) α significantly reduced apoptosis. We investigate further the suppression of endothelial apoptosis by shear stress with other apoptotic triggers, and the involvement of DAPK and caspase 3/7.ResultsWe have shown that exposure to shear stress (12 dynes/cm2 for 6 hrs) suppressed endothelial apoptosis triggered by cytokine (TNFα), oxidative stress (H2O2), and serum depletion, either before or after a long term (18 hr) induction. This is correlated with a parallel decrease of DAPK expression and caspase activity compared to non-sheared cells. We found similar modulation of DAPK and apoptosis by shear stress with other pro-apoptotic signals. Changes in DAPK and caspase 3/7 are directly correlated to changes in apoptosis. Interestingly, shear stress applied to cells prior to induction with apoptosis agents resulted in a higher suppression of apoptosis and DAPK and caspase activity, compared to applying shear stress post induction. This is correlated with a higher expression and activation of DAPK in cells sheared at the end of 24-hr experiment. Also, shear stress alone also induced higher apoptosis and DAPK expression, and the effect is sustained even after 18 hrs incubation in static condition, compared to non-sheared cells.ConclusionsOverall, we show that laminar shear stress inhibits various apoptosis pathways by modulating DAPK activity, as well as caspase activation, in a time-dependent manner. Shear stress could target DAPK as a converging point to exert its effects of suppressing endothelial apoptosis. The temporal shear stress stimulation of DAPK and its role in different apoptosis pathways may help identify key mechanisms of the endothelial mechanotransduction pathway.

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The role of death-associated protein kinase (DAPK) in endothelial apoptosis under fluid shear stress

Cited by 13 publications

References 81 publications

Death‐associated protein kinase (DAPK) family modulators: Current and future therapeutic outcomes

Death‐associated protein kinase (DAPK) family modulators: Current and future therapeutic outcomes

Altered gene expression in T-cell receptor signalling in peripheral blood leucocytes in acute coronary syndrome predicts secondary coronary events

Shear stress attenuates apoptosis due to TNFα, oxidative stress, and serum depletion via death-associated protein kinase (DAPK) expression

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