Dataset Information

Cyclin-dependent kinase 5 contributes to apoptosis of vascular endothelial cells during aortic dissection.

ABSTRACT:

Background

Tearing of inner layer of aorta causes aortic dissection (AD), a severe disease with high morbidity and mortality. The pathological development of AD partially results from apoptotic death of aortic endothelial cells (AECs), the trigger and the molecular regulation of which remain largely unknown. Cyclin-dependent kinase 5 (CDK5) was initially detected in the brain as a proline-directed serine/threonine protein kinase regulating neuronal cell cycle re-entry and arrest. The abnormal expression of CDK5 leads to apoptotic cell death following abortive cell cycle re-entry in some neuronal diseases. Although physiological and pathological roles of CDK5 have been widely investigated, the expression and function of CDK5 in AD have not been reported. Therefore, the aim of the present study was to discuss the expression and function of CDK5 in AD.

Methods

Gene expression profiles were compared between AD tissues and normal aortic tissues using Gene Expression Omnibus (GEO) database with bioinformatic tools. Different cell types were isolated from the digested AD and normal aortic specimens by fluorescence-activated cell sorting (FACS). Gene expression in cells was quantified by quantitative reverse transcription polymerase chain reaction. Endothelial cells purified by FACS were transfected in vivo with plasmids. Cell growth was analyzed by Cell Counting Kit-8 assay. Cell apoptosis was analyzed by terminal deoxynucleotidyl transferase-mediated digoxigenin-dUTP nick-end labeling assay.

Results

Analysis of gene profiles from AD tissues and normal aortic tissues using GEO database showed significant higher expression of CDK5 and its downstream regulated genes, proliferating cell nuclear antigen, cyclin B1, and B-cell lymphoma 2, which are regulators for cell cycle and apoptosis. Analysis of purified cells from AD and normal aortic specimens further confirmed this result and showed that the major source of CDK5 was endothelial cells. Depletion of CDK5 inhibited apoptosis of AECs, while the expression of CDK5 promoted apoptosis of AECs.

Conclusions

CDK5 induces apoptosis of AECs to promote AD. CDK5 appears to be a promising novel target for preventing AD.

SUBMITTER: Huang J

PROVIDER: S-EPMC9469115 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Publications

Cyclin-dependent kinase 5 contributes to apoptosis of vascular endothelial cells during aortic dissection.

Huang Jingyong J Lemaire Anthony A Huang Chongqing C

Annals of translational medicine 20220801 16

<h4>Background</h4>Tearing of inner layer of aorta causes aortic dissection (AD), a severe disease with high morbidity and mortality. The pathological development of AD partially results from apoptotic death of aortic endothelial cells (AECs), the trigger and the molecular regulation of which remain largely unknown. Cyclin-dependent kinase 5 (CDK5) was initially detected in the brain as a proline-directed serine/threonine protein kinase regulating neuronal cell cycle re-entry and arrest. The abn ...[more]

PMID: 36110999

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Project description:ImportanceVascular endothelial growth factor pathway inhibitors (VPIs) pose a concern for aortic aneurysm (AA) and aortic dissection (AD), signaling potential vascular disease development.ObjectiveTo investigate VPI-associated AA and AD.Design, setting, and participantsThis case-control study with a nested design used full population data from a national claims database in Taiwan between 2011 and 2019. Eligible participants were aged 20 years or older with kidney, hepatic, gastrointestinal, or pancreatic cancer diagnosed between January 1, 2012, and December 31, 2019. The first cancer diagnosis date was defined as the cohort entry date. Cases were patients who received a diagnosis of AA or AD in hospitalizations or emergency visits between the cohort entry date and December 31, 2019. Controls were matched by ratio (up to 1:5) based on age, sex, cancer type, cohort entry date, and the index date (ie, the first AA or AD event date). Data analysis was performed between January 2022 and December 2023.ExposuresUse of the oral VPIs sorafenib, sunitinib, and pazopanib between cohort entry date and index date.Main outcomes and measuresIn the primary analysis, AA and AD were evaluated compositely, while in the secondary analyses, they were evaluated separately. Adjusted odds ratios (aORs) were calculated using conditional logistic regression to assess the association with VPI use (sorafenib, sunitinib, and pazopanib) considering various VPI exposure windows and cumulative use.ResultsA total of 1461 cases were included (mean [SD] age, 73.0 [12.3] years; 1118 male patients [76.5%]), matched to 7198 controls. AA or AD risk increased with a VPI exposure of 100 days or less before the index date (aOR, 2.10; 95% CI, 1.40-3.15), mainly from VPI-associated AD (aOR, 3.09; 95% CI, 1.77-5.39). Longer VPI duration (68 days or more: aOR, 2.64; 95% CI, 1.66-4.19) and higher cumulative dose (61 or more defined daily doses: aOR, 2.65; 95% CI, 1.66-4.23) increased the risk.Conclusions and relevanceThe use of the 3 study VPIs (sorafenib, sunitinib, and pazopanib) was associated with an increased risk of AA and AD in patients with cancer, essentially all of the risk from VPI-associated AD. Future studies are needed to determine the risk factors of VPI-associated AA and AD, as well as to establish a class effect.

Dataset Information

Cyclin-dependent kinase 5 contributes to apoptosis of vascular endothelial cells during aortic dissection.

Background

Methods

Results

Conclusions

Publications

Cyclin-dependent kinase 5 contributes to apoptosis of vascular endothelial cells during aortic dissection.

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