A novel role for the plasma membrane calcium pump (PMCA1) in cardiomyopathy and blood pressure control
Lead Research Organisation:
University of Manchester
Department Name: Medical and Human Sciences
Abstract
Heart failure affects around 1 million people in the UK, patient numbers are rising rapidly and survival is similar to that of some cancers. Heart failure patients are known to die from two main causes, either pump failure or heartbeat abnormalities (arrhythmias). In addition, high blood pressure (hypertension) greatly aggravates heart failure.
Improving treatment of heart failure, which currently is highly unsatisfactory, is the main motivation for our research. We have shown that a gene called the plasma membrane calcium pump isoform 1 (PMCA1) is central to all three key features of heart failure ? pump failure, arrhythmias and hypertension. By transporting calcium out of the cell PMCA1 helps the heart muscle to relax and blood pressure to fall. Strongly supporting our approach, recent genetic studies in humans have shown that PMCA1 is key to human disease. Our programme will take these findings to the next essential level, i.e. understanding the function of PMCA1. To this end we will study mouse models in which the level of PMCA1 in the heart and vessels has been genetically modified. This programme is pivotal for understanding heart failure and hypertension and will provide information essential to the development of new treatments.
Improving treatment of heart failure, which currently is highly unsatisfactory, is the main motivation for our research. We have shown that a gene called the plasma membrane calcium pump isoform 1 (PMCA1) is central to all three key features of heart failure ? pump failure, arrhythmias and hypertension. By transporting calcium out of the cell PMCA1 helps the heart muscle to relax and blood pressure to fall. Strongly supporting our approach, recent genetic studies in humans have shown that PMCA1 is key to human disease. Our programme will take these findings to the next essential level, i.e. understanding the function of PMCA1. To this end we will study mouse models in which the level of PMCA1 in the heart and vessels has been genetically modified. This programme is pivotal for understanding heart failure and hypertension and will provide information essential to the development of new treatments.
Technical Summary
Heart failure (HF) currently affects around 1 million people in the UK leading to an annual financial burden on the health services of over #1 billion, and its incidence is rising rapidly. HF has a dismal prognosis, with patients dying from progressive pump failure or ventricular arrhythmias. Hypertension, which affects around 15% of the general population, is strongly associated with heart failure with 80% of HF patients having hypertension.
PMCA1 is a member of a family of four transmembrane calcium transporters that eject calcium from the cell, but whose exact (patho)physiological function remains unknown.
We have made the unexpected finding that PMCA1 is involved in all of the central features of heart failure: cardiomyopathy, arrhythmias and hypertension:
? Our cardiomyocyte-specific PMCA1 knockout mice(PMCA1cko) develop severe cardiomyopathy with HF and lethal rhythm disorders. Rhythm disorders occur before ventricular dilatation suggesting a highly specific mechanism.
? Our heterozygote global PMCA1 knockout mice(PMCA1Ht) have raised blood pressure (homozygotes are not viable).
? Three recent genome wide association studies (White, Korean and Japanese populations) by others have identified single nucleotide polymorphisms in the PMCA1 gene as the single strongest association with blood pressure variance in humans.
It is the purpose of the present programme to determine the mechanisms underlying the role of PMCA1 in heart failure and high blood pressure at the whole animal, organ as well as at the cellular/molecular level.
To this end, we will use our tissue-specific (cardiomyocyte, vascular smooth muscle) PMCA1 knockout mice as well as state-of-the-art in vivo haemodynamic, electrophysiological, functional and molecular techniques. We have 20 years of experience with the molecular biology and (patho)physiology of the plasma membrane calcium pumps; all requisite techniques are long established in our group and we are leaders in the field. This leadership has been recognised and facilitated by MRC International Appointee and programme grant funding since 2001, which has been on PMCA4, an independent isoform of the calcium pump with entirely different functions.
This programme is at the heart of the research priorities of the MRC. Firstly, research into heart failure, ventricular arrhythmias and hypertension have been key areas of MRC funding over many years. Secondly, understanding the function of the genes underlying the genetic components of disease (physiological genomics) has been defined as a focus of the MRC (Theme 2, ?Living a long and healthy life?, ?Genetics and Disease?).
PMCA1 is a member of a family of four transmembrane calcium transporters that eject calcium from the cell, but whose exact (patho)physiological function remains unknown.
We have made the unexpected finding that PMCA1 is involved in all of the central features of heart failure: cardiomyopathy, arrhythmias and hypertension:
? Our cardiomyocyte-specific PMCA1 knockout mice(PMCA1cko) develop severe cardiomyopathy with HF and lethal rhythm disorders. Rhythm disorders occur before ventricular dilatation suggesting a highly specific mechanism.
? Our heterozygote global PMCA1 knockout mice(PMCA1Ht) have raised blood pressure (homozygotes are not viable).
? Three recent genome wide association studies (White, Korean and Japanese populations) by others have identified single nucleotide polymorphisms in the PMCA1 gene as the single strongest association with blood pressure variance in humans.
It is the purpose of the present programme to determine the mechanisms underlying the role of PMCA1 in heart failure and high blood pressure at the whole animal, organ as well as at the cellular/molecular level.
To this end, we will use our tissue-specific (cardiomyocyte, vascular smooth muscle) PMCA1 knockout mice as well as state-of-the-art in vivo haemodynamic, electrophysiological, functional and molecular techniques. We have 20 years of experience with the molecular biology and (patho)physiology of the plasma membrane calcium pumps; all requisite techniques are long established in our group and we are leaders in the field. This leadership has been recognised and facilitated by MRC International Appointee and programme grant funding since 2001, which has been on PMCA4, an independent isoform of the calcium pump with entirely different functions.
This programme is at the heart of the research priorities of the MRC. Firstly, research into heart failure, ventricular arrhythmias and hypertension have been key areas of MRC funding over many years. Secondly, understanding the function of the genes underlying the genetic components of disease (physiological genomics) has been defined as a focus of the MRC (Theme 2, ?Living a long and healthy life?, ?Genetics and Disease?).