Doxorubicin triggers endothelial dysfunction by downregulation KLF2 expression: strategeis for pharmacologic intervention.

Voskuil, F.J (2014) Doxorubicin triggers endothelial dysfunction by downregulation KLF2 expression: strategeis for pharmacologic intervention. thesis, Medicine.

Text VoskuilF.pdf Download (2MB)

Abstract

Introduction: Doxorubicin (DOX) is a widely used chemotherapeutic agent. Despite its high anticancer capacities, DOX is notorious for its strong side effects. Common DOX associated side effects are cardiotoxicity and palmar-plantar erythrodysesthesia (PPE). Recently, it’s determined that DOX causes endothelial injury, however, the exact mechanisms remain unknown. Since it’s known that Kruppel-like factor 2 (KLF2) plays a crucial role in maintaining endothelial function, there might be a potential role for KLF2 in the DOX-induced side effects. In this study, we examined the role of KLF2 in the DOX-induced endothelial damage, and the possibility for pharmacological intervention by statins. Materials and Methods: Primary human umbilical vein endothelial cells (HUVECs) were used to determine the expression of KLF2 and its target genes after DOX treatment. To investigate if DOX treatment leads to apoptosis in ECs, we used both a MTT and flow cytometry assay to quantify apoptosis in DOX-treated cells. In addition, we evaluated the expression of vasoprotective genes under vasoprotective shear stress conditions, using a previously developed Dynamic Flow System (DFS). Moreover, we evaluated the effect of Simvastatin treatment prior and simultaneously on DOX treatment. Results: The expression of KLF2 and its vasoprotective transcriptional target genes, as well as other endothelial vasoprotective genes were significantly altered after DOX treatment at different concentrations under static culture conditions. The MTT assay showed that there was no significant difference between the used concentrations and the vehicle in regard to cell death. In addition, flow cytometry analyses documented that there was no difference in apoptotic cells between DOX treated and untreated cells. The expression of KLF2 in the vasoprotective shear stress environment was curtailed after DOX treatment, and angiopoietin-2 (Ang-2) was strongly upregulated. Importantly, we also showed that the effect of DOX on vasoprotective genes can be rescued after statin treatment. Conclusions: DOX treatment in HUVECs leads to an important change in the expression of vasoprotective genes. Moreover, we show that statins could rescue the gene alterations when administrated simultaneously, which might be an easy implementable addition to DOX treatment in the clinical setting. However, in vivo experiments, and human trials need to be done to draw final conclusions.

Item Type:	Thesis (Thesis)
Supervisor name:	Son, Prof. Dr. W.J. van and Leuvenink, Dr H.G.D.
Supervisor name:	Tullius, S.G. MD PhD and Garcia-Cardena, G. PhD and Harvard Medical School, USA
Faculty:	Medical Sciences
Date Deposited:	25 Jun 2020 11:02
Last Modified:	25 Jun 2020 11:02
URI:	https://umcg.studenttheses.ub.rug.nl/id/eprint/2177

Actions (login required)

View Item