| dc.contributor.advisor | Schäfer, Katrin Prof. Dr. | |
| dc.contributor.author | Gogiraju, Rajinikanth | |
| dc.date.accessioned | 2015-01-21T10:57:06Z | |
| dc.date.available | 2015-03-31T22:50:05Z | |
| dc.date.issued | 2015-01-21 | |
| dc.identifier.uri | http://hdl.handle.net/11858/00-1735-0000-0022-5D8C-0 | |
| dc.identifier.uri | http://dx.doi.org/10.53846/goediss-4713 | |
| dc.language.iso | eng | de |
| dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/3.0/ | |
| dc.title | Endothelial Transformation Related Protein 53 Deletion Promotes Angiogenesis and Prevents Cardiac Fibrosis and Heart Failure Induced by Pressure Overload in Mice | de |
| dc.type | doctoralThesis | de |
| dc.contributor.referee | Dobbelstein, Matthias Prof. Dr. | |
| dc.date.examination | 2014-09-10 | |
| dc.description.abstracteng | Background− Accumulation of transformation related protein 53 (p53), apoptotic cell death and rarefication of myocardial angiogenesis may be involved in the development of cardiac dysfunction during chronic pressure overload.
Objective− The aim of this study was to determine whether prevention of endothelial cell apoptosis deletion of p53 in endothelial cells improves cardiac remodeling during pressure overload and prevents the transition from hypertrophy to heart failure.
Methods and Results− Mice with endothelial deletion of p53 (End.p53-KO) were generated by crossing p53fl/fl mice with mice expressing Cre recombinase under control of an inducible Tie2 promoter. Cardiac hypertrophy was induced by transverse aortic constriction. Serial echocardiography measurements revealed improved cardiac function and survival in End.p53-KO mice. In End.p53-WT controls, cardiac hypertrophy was associated with increased p53 levels, whereas banded hearts of End.p53-KO mice exhibited lower apoptotic cell numbers, both in endothelial and non-endothelial cells. Moreover, a higher cardiac capillary density, improved perfusion and elevated Hif1 and Vegf protein levels were observed, and inhibition or deletion of p53 also promoted endothelial sprouting in vitro and new vessel formation following hindlimb ischemia in vivo. Hearts of End.p53-KO mice exhibited markedly less interstitial fibrosis compared to End.p53-WT controls, and lower mRNA levels of p53-regulated genes involved in extracellular matrix production and turnover, or transcription factors involved in endothelial-to-mesenchymal transition.
Conclusions− Our data suggest that accumulation of p53 in endothelial cells contributes to cardiac apoptosis, blood vessel rarefication and fibrosis during chronic pressure overload and support the essential role of endothelial cells and cardiac angiogenesis for preserving contractile function during hypertrophy. | de |
| dc.contributor.coReferee | Kessel, Michael Prof. Dr. | |
| dc.contributor.thirdReferee | Zimmermann, Wolfram-Hubertus Prof. Dr. | |
| dc.contributor.thirdReferee | Zeisberg, Michael Prof. Dr. | |
| dc.contributor.thirdReferee | Lutz, Susanne Prof. Dr. | |
| dc.subject.eng | angiogenesis | de |
| dc.subject.eng | apoptosis | de |
| dc.subject.eng | endothelium | de |
| dc.subject.eng | fibrosis | de |
| dc.subject.eng | heart failure | de |
| dc.identifier.urn | urn:nbn:de:gbv:7-11858/00-1735-0000-0022-5D8C-0-1 | |
| dc.description.embargoed | 2015-03-31 | |
| dc.identifier.ppn | 815977360 | |