Analysing the role of statins in cardiovascular protection

Description

Drug-induced cardiovascular toxicity is a major problem affecting a number of cancer chemotherapy drugs (Cross et al., 2015). Due to the increasing number of patients treated by chemotherapy and biological drugs (often in combination and at progressively higher cumulative doses), the incidence of cardiotoxicity is continuously growing. The inherent lack of significant cardiac regenerative capacity means that damage to the heart is often accumulative and irreversible, potentially manifesting many years after chemotherapy treatment has finished in patients. Drug-induced cardiovascular toxicity can occur with a range of cancer drugs, such as the anthracycline doxorubicin, trastuzumab (Herceptin) and cyclophosphamide (Yeh, et al., 2009).

Doxorubicin is used to treat a number of malignancies, ranging from leukaemia in children through to breast cancer in women. However, despite its efficacy against cancer, drug-induced cardiovascular toxicity is a major problem with doxorubicin, with up to 26% of patients showing reduced left ventricular ejection fraction (LVEF) (Yeh, et al., 2009).

Recent data from our group have shown that doxorubicin treatment of cardiac endothelial cells results in loss of tight junctional complexes, suggesting that cardiotoxicity and cardiomyopathy could be a secondary effect caused by a leaky cardiac microvasculature (Wilkinson et al., 2016). Furthermore, our in vitro studies have revealed that statins, have the capacity to counteract the loss of tight junctions in Dox-treated cardiac endothelial cells via activation of the ERK5 protein kinase (Wilkinson et al., 2018). Statins have been widely used to lower LDL-cholesterol levels in patients via inhibition of HMG CoA-reductase, a rate-limiting enzyme in the mevalonate pathway leading to cholesterol biosynthesis in the liver. Studies in mice have shown that pre-treatment with statins can protect against doxorubicin-induced cardiotoxicity, an effect attributed to direct effects on cardiomyocytes.  Our project aim is to use in vitro and in vivo studies to evaluate the vascular protective effect of statins.

This project will initially utilise primary human cardiac microvascular endothelial cells (HCMECs) to investigate the vascular protective pathways stimulated by statins. siRNA mediated gene silencing and reporter assays will be used to identify the signalling pathways downstream of HMG CoA-reductase inhibition leading to activation of ERK5 and a vascular protective effect.  The project will progress to using a mouse model of doxorubicin-induced cardiac injury to investigate the ability of statins to protect against doxorubicin injury in vivo.

Student experience

The student will be based in a dynamic research environment with modern research laboratories and office space. The student will be trained in a comprehensive range of in vitro and in vivo techniques, including primary human cell culture, siRNA mediated gene silencing, Western Blotting, mouse cardiac MRI and ultrasound analysis, and immunofluorescence analysis of mouse cardiac tissue sections.

Research Environment

The student will be embedded in a vibrant and well funded research environment. Our research involves collaboration with a range of academic partners and pre-clinical imaging specialists.

Applicant Information

The successful applicant should have an interest in basic biomedical and toxicology research and hold a minimum undergraduate qualification 2:1, or equivalent, in a life science or health-related subject.

Research project related enquiries should be made in the first instance to Dr. Michael Cross (m.j.cross@liverpool.ac.uk).

To apply please send your CV and a covering letter to Dr Michael Cross (m.j.cross@liverpool.ac.uk).