The role of cardiac microvascular endothelial cells in drug induced cardiovascular toxicity

Smith, Emma
The role of cardiac microvascular endothelial cells in drug induced cardiovascular toxicity. PhD thesis, University of Liverpool.

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Cardiovascular toxicity is defined as a severe and potentially fatal adverse reaction to certain drugs. It is one of the leading causes of attrition in drug development. Cardiovascular toxicity research has primarily focused on the role of cardiomyocytes in functional and structural cardiovascular toxicity. However, there is a growing awareness that non-myocyte cells may contribute to cardiovascular toxicity. The heart is a highly vascularised organ. Endothelial cells from the heart were compared between rat and human, as well as between different vascular beds with the use of human cardiac microvascular endothelial cells (HCMECs) and human dermal microvascular endothelial cells (HDMECs). This data demonstrated ligand induced activation of EGFR-1 in HCMEC indicating the presence of functional EGFR1. Analysis of mRNA expression of EGFR1-4 revealed higher expression of both EGFR1 and EGFR2 in HCMEC compared with HDMEC. The role of EGFR-2 (Her2) in drug-induced cardiovascular toxicity was analysed with use of Herceptin® and doxorubicin treatment. Herceptin® and doxorubicin are known to induce cardiovascular toxicity in the clinic. The effect of these drugs on the endothelial tight junction barrier was tested, revealing that Herceptin® and doxorubicin are able to induce barrier perturbment and decreased barrier function in HCMEC. Herceptin® treatment had no effect on the tight junction barrier function in HDMECs. Previous work in the group has identified a role for extracellular-signal-regulated kinase 5 (ERK5) in regulation of endothelial cell survival. The role of ERK5 in endothelial tight junction regulation was investigated using small molecule inhibitors, siRNA transient gene silencing and adenoviral–mediated overexpression of ERK5 to reveal that ERK5 plays an important role in tight junction regulation and endothelial barrier function. Statins are clinically used to lower plasma LDL-cholesterol levels in patients via inhibition of 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-CoA reductase). Simvastatin activated ERK5 in endothelial cells via a pathway requiring MEKK3 and MEK5 leading to increased tight junction formation and increased barrier function, providing a possible mechanism for the pleiotropic effects of statins on endothelial cells. Analysis of the effects of a range of anti-cancer drugs with known cardiovascular toxicity liability revealed these drugs could disrupt tight junctions and decrease barrier function. Pre-incubation with simvastatin protected the endothelial cells from drug induced perturbment of endothelial tight junction formation and the associated decrease in barrier function. The data shows the importance of drug-induced endothelial injury in cardiovascular toxicity and highlights potential for therapeutically targeting vasculature to protect against drug-induced vascular injury.

Item Type: Thesis (PhD)
Additional Information: Date: 2015-07 (completed)
Depositing User: Symplectic Admin
Date Deposited: 15 Jan 2016 15:34
Last Modified: 17 Dec 2022 01:18
DOI: 10.17638/02036460