The role of Nrf2 (nuclear factor erythroid 2 related factor 2) in the cardiac response to chronic overload stress.

Lead Research Organisation: King's College London
Department Name: Cardiovascular

Abstract

Heart failure is a leading cause of morbidity and mortality. New treatments are required to address this growing problem. Understanding the mechanisms involved in the development of heart failure is the key to developing new treatments. When a heart is under prolonged stress, such as high blood pressure, it initially adapts to preserve its function. However, with time, its strength declines and heart failure ensues. A complex interplay between protective and damaging cellular pathways determines whether the heart adapts or fails. This project will study the role of a master regulator of genes, known as Nrf2, which we believe may play a key role in activating protective pathways in the heart. The project will study the role of Nrf2 in protecting the heart during exposure to chronic high blood pressure and will investigate the pathways activated by Nrf2 that are involved in such protection. By using state-of-the-art methodology to analyse the complex changes coordinated and regulated by Nrf2, we hope that the project will provide novel insights into key mechanisms involved in the development of heart failure and therefore lead to the identification of novel therapeutic targets for this debilitating condition.

Technical Summary

Background: Patients with chronic heart failure have substantial morbidity and mortality and new therapies for the condition are required. An imbalance between the production of reactive oxygen species (ROS) and antioxidant defences - known as oxidative stress - is known to be involved in the pathophysiology of heart failure. Recent studies indicate that ROS may regulate both detrimental pathways and protective pathways (e.g. angiogenesis) involved in the cardiac response to chronic stress. The balance between these pathways determines whether the heart adapts to stress or fails. Preliminary studies in genetic models with enhanced protection against chronic stress suggest that ROS-dependent activation of the transcription factor Nrf2 may be an important component of adaptive pathways activated by chronic overload. Nrf2 coordinates the expression of a large number of antioxidant and other cytoprotective proteins and is critical in regulating redox homoeostasis. It is known to be important in cytoprotection in many tissues during cellular stress but its possible role in the heart remains poorly studied.
Hypothesis: The activation of Nrf2 and Nrf2-activated genes is a key adaptive mechanism in the cardiac response to chronic overload stress.
Aims of project: (1) To establish the role of cardiomyocyte Nrf2 in the cardiac response to chronic overload stress; (2) To investigate the mechanisms involved in Nrf2-dependent protection against cardiac stress.
Project objectives, design and methodology: Studies will be undertaken in novel genetic models in which Nrf2 has been specifically deleted in cardiomyocytes. Chronic overload stress will be imposed in Nrf2 knockout and control models by transverse aortic constriction and the cardiac response studied during the development of cardiac hypertrophy and failure. Analyses will be undertaken of cardiac remodelling, ROS production, antioxidant and cytoprotective genes, redox homeostasis and key signalling pathways involved in remodelling - using echocardiography, histology, RT-PCR, immunoblotting and biochemical assays. To study putative mechanisms involved in Nrf2-dependent protection, the following will be studied: myocardial apoptosis, angiogenesis, inflammation, and mitochondrial biogenesis. To assess the interactions among different Nrf2-regulated pathways and processes, a combined transcriptomic/proteomic/metabolomic analysis will also be undertaken.
Scientific and medical value: The project will establish the role of Nrf2 in the cardiac response to chronic stress and provide novel data on Nrf2-regulated pathways in the heart. It may lead to the identification of novel therapeutic targets for the prevention and/or treatment of heart failure.

Publications


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Description BRC Early Career Award
Amount £4,000 (GBP)
Organisation King’s Health Partners 
Sector Academic/University
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 01/2012 
End 01/2013