The sarcolemmal calcium signalling protein PMCA4 as a novel target to reduce cardiac hypertrophy and failure
Lead Research Organisation:
University of Manchester
Department Name: Medical and Human Sciences
Abstract
Heart failure affects nearly 1 million people in the UK alone. Heart failure is a condition in which the heart can no longer supply the tissues of the body with enough blood to meet its metabolic demands. Despite recent progress in the treatment of this condition prognosis remains very poor, with 2-5% of the population likely to die from heart failure. It is therefore essential that we understand how and why this condition develops in order to develop better treatment strategies. Heart failure develops following an insult to the heart such as high blood pressure or a heart attack, this will lead to enlargement of the heart muscle, known as hypertrophy, before progressing to heart failure.
As a result of previous funding from the MRC we have determined that by deleting the plasma membrane calcium pump (PMCA4) gene from the cells of the heart in a mouse model that we can protect the heart from developing hypertrophy (muscle enlargement) and ultimately heart failure.
In the proposed programme of work we aim to determine how and why deletion of PMCA4 protects the heart from hypertrophy and heart failure. We will also determine whether this gene is involved in the development of disease in heart failure patients. In the future it may be possible to treat heart failure patients with a drug to stop the action of the PMCA4 protein and therefore protect these patients from heart failure; in this project we will take the first steps to identify a substance which would have this desired effect.
As a result of previous funding from the MRC we have determined that by deleting the plasma membrane calcium pump (PMCA4) gene from the cells of the heart in a mouse model that we can protect the heart from developing hypertrophy (muscle enlargement) and ultimately heart failure.
In the proposed programme of work we aim to determine how and why deletion of PMCA4 protects the heart from hypertrophy and heart failure. We will also determine whether this gene is involved in the development of disease in heart failure patients. In the future it may be possible to treat heart failure patients with a drug to stop the action of the PMCA4 protein and therefore protect these patients from heart failure; in this project we will take the first steps to identify a substance which would have this desired effect.
Technical Summary
Heart Failure (HF) is one of the most prevalent causes of mortality globally, but its mechanisms are incompletely understood and treatment remains unsatisfactory. As a result of our MRC funded work on the mechanisms of calcium signalling in HF (Int. Appointee Grant, 2002-5, and subsequent programme grant, 2006-9) we have shown that the Plasma Membrane Calmodulin-dependent Calcium ATPase (PMCA4), whose role had been unknown, has a major role in physiological cardiac signalling by regulating neuronal NOS and the beta-adrenergic response. We have recently made the key finding that deletion of PMCA4 in vivo completely abolishes the pathological cardiac hypertrophic response, which underlies the development of HF.
The present programme will:
A. Start to define the mechanisms through which deletion of PMCA4 abolishes pathological cardiac hypertrophy and failure.
B. Start to define the role of PMCA4 in human cardiac pathophysiology.
C. Generate and initially test PMCA4 inhibitors.
The results will:
? Assign, for the first time, a specific signalling role to a cardiac membrane calcium transport system, i.e. PMCA4, in cardiac hypertrophy. This work will considerably increase our understanding of the mechanistic basis for calcium signalling in the normal and failing heart.
? Provide evidence for the translation of these findings to human heart failure.
? Provide key tools that are currently not available for calcium research in the heart and in other fields, i.e. inhibitors with preferential specificity for PMCA4. This will lay the basic science foundations for potential future medical use of PMCA4 inhibitors in heart failure thus considerably narrowing the ?early funding gap? between basic science and translation into application, a major goal of MRC research funding.
The present programme will:
A. Start to define the mechanisms through which deletion of PMCA4 abolishes pathological cardiac hypertrophy and failure.
B. Start to define the role of PMCA4 in human cardiac pathophysiology.
C. Generate and initially test PMCA4 inhibitors.
The results will:
? Assign, for the first time, a specific signalling role to a cardiac membrane calcium transport system, i.e. PMCA4, in cardiac hypertrophy. This work will considerably increase our understanding of the mechanistic basis for calcium signalling in the normal and failing heart.
? Provide evidence for the translation of these findings to human heart failure.
? Provide key tools that are currently not available for calcium research in the heart and in other fields, i.e. inhibitors with preferential specificity for PMCA4. This will lay the basic science foundations for potential future medical use of PMCA4 inhibitors in heart failure thus considerably narrowing the ?early funding gap? between basic science and translation into application, a major goal of MRC research funding.
