| dc.contributor.advisor | Pantakani, Dasaradha Venkata Krishna Dr. | |
| dc.contributor.author | Shahid, Sidra | |
| dc.date.accessioned | 2019-03-15T11:54:39Z | |
| dc.date.available | 2020-02-12T23:50:03Z | |
| dc.date.issued | 2019-03-15 | |
| dc.identifier.uri | http://hdl.handle.net/11858/00-1735-0000-002E-E5D3-1 | |
| dc.identifier.uri | http://dx.doi.org/10.53846/goediss-7328 | |
| dc.language.iso | eng | de |
| dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | |
| dc.subject.ddc | 570 | de |
| dc.title | Role of BRD4 and its target Ptp1b in Endothelial cells and in cardiovascular disease models | de |
| dc.type | doctoralThesis | de |
| dc.contributor.referee | Adham, Ibrahim Prof. Dr. | |
| dc.date.examination | 2019-02-13 | |
| dc.description.abstracteng | Vascular and lymphatic system is lined by Endothelial cells (ECs) monolayer or endothelium. Healthy endothelium maintains vessel functions by releasing different substances including Nitric Oxide (NO). Cardiovascular risk factors induce ECs dysfunction, which leads to the increase permeability of ECs and development of atherosclerosis. In response to inflammatory stimulus, NF-κB signalling pathway becomes activated. NF-κB signalling is responsible for releasing cytokines and expressing adhesion molecules on ECs surface. BRD4 is a chromatin regulator transcription factor, which binds to super enhancers of basal cell state maintaining gene loci. BRD4 redistributes on chromatin during inflammation and along with NF-κB binds to super enhancers of inflammatory gene loci.
In the present study, we analysed the role of BRD4 and its isoforms in ECs dysfunction and investigated whether BRD4 inhibition restores ECs function under inflammation-stimulating conditions. We established an in vitro model of inflammatory phenotype using he treatment of HUVECs with TNF-α. Our study indicates that BRD4 short isoform is overexpressed in HUVECs during inflammation along with increased expression of inflammatory markers, Midkine, and PTP1B. Pre-treatment with BRD4 inhibitors (JQ1 and RVX-208) abrogates ECs activation and dysfunction via reducing the expression of pro inflammatory markers. We also observed that TNF-α treated HUVECs showed increased permeability which indicates disrupted monolayer integrity. In contrast, monolayer integrity was retained when HUVECs pre-treated with BRD4 inhibitors.
Elevated levels of Midkine has been reported in human and mice atherosclerotic plaques. It has also been reported to disrupt monolayer integrity via activation of downstream signalling pathways. HUVECs secrete Midkine when treated to 48-72 hours with TNF-α. BRD4 inhibition with JQ1 and RVX208 reduced the Midkine secretion indicating BRD4 inhibition is retaining the monolayer integrity by reduce Midkine signalling. As far as we know, this is the first study that identified the role of BRD4 in regulation of Midkine, an upstream regulator of p38MAPK signalling pathway. Our data pointed out that an orally administered RVX208 drug can contribute in atherosclerosis treatment. Our study gives an indication that BRD4 inhibition can be used as a therapeutic option for treatment of atherosclerosis. Our results confirms the previous observations stating PTP1B inhibition is beneficial in ECs, in-vitro and in-vivo. This is the first study to report the heart global proteome of PTP1B-deficient mice and its contribution in prevention of cardiac fibrosis and hypertrophy. Our data shed light on cardio-protective role of PTP1B deletion by identifying the improvement of mitochondrial function in cardiac hypertrophy animals. Furthermore, this report proved in in-vitro study that PTP1B inhibition improves the ATP production in ECs. From our results, it can be suggested that PTP1B inhibition can be a therapeutic option in prevention of cardiac fibrosis and hypertrophy after myocardial infarction. This study provides essential understanding into beneficial roles of BRD4 and Ptp1b in CVDs, especially, atherosclerosis and cardiac hypertrophy. | de |
| dc.contributor.coReferee | Hoyer-Fender, Sigrid Prof. Dr. | |
| dc.subject.eng | BRD4 | de |
| dc.subject.eng | Midkine | de |
| dc.subject.eng | Ptp1b proteomics | de |
| dc.subject.eng | Endothelial cells dysfunction | de |
| dc.identifier.urn | urn:nbn:de:gbv:7-11858/00-1735-0000-002E-E5D3-1-4 | |
| dc.affiliation.institute | Biologische Fakultät für Biologie und Psychologie | de |
| dc.subject.gokfull | Biologie (PPN619462639) | de |
| dc.description.embargoed | 2020-02-12 | |
| dc.identifier.ppn | 1685514499 | |