Abstract The role of PMCA1 in the development of heart failure Heart Failure remains a major cause of morbidity and mortality worldwide. Whilst a number of pharmacological treatments are used in heart failure management, there is no targeted therapy available to tackle the cardiac remodelling that often precedes decompensated heart failure. Plasma membrane calcium ATPase 1 (PMCA1) is the most prevalent isoform of PMCA in the heart, and human genome wide association studies have shown a link between PMCA1 and hypertension and other cardiovascular diseases. Previous work from our group has provided functional evidence of the association between reduced PMCA1 expression and hypertension and cardiac arrhythmias in murine models. Our group have previously generated two novel PMCA1 mutant mouse lines using Cre/loxP technology including a cardiomyocyte specific deletion (PMCA1cko) and a global heterozygous deletion (PMCA1HT), both of which show reduced expression of PMCA1. This study was designed to explore the role played by PMCA1 in heart failure and to evaluate cardiac remodelling in mice with reduced expression of PMCA1. For this study, eight week old PMCA1cko mice were subjected to transverse aortic constriction (TAC) or sham operation for a period of two weeks along with their age and gender-matched controls. In a separate experiment, eight week old male PMCA1HT mice and their controls were subjected to transverse aortic constriction (TAC) and sham operation for a period of five weeks. In TAC procedure, the transverse aorta was ligated (over a curved blunt 27G needle) between the brachiocephalic trunk and the left common carotid artery using a surgical suture that produces approximately 25% narrowing of the aortic lumen, whilst in mice undergoing the sham operation the aorta was exposed and a surgical suture passed around it but not ligated. Echocardiogram and haemodynamic analysis were performed at the end of the experiment and animals were sacrificed. Cardiac tissue samples were collected for histology, qPCR and proteomic analysis. Under basal physiological conditions, no significant difference was found in the cardiac structure and function of the transgenic (PMCA1cko and PMCA1HT) and control mice. Two weeks after TAC, PMCA1cko mice developed decompensated heart failure with evidence of left ventricular dilatation, systolic dysfunction and pulmonary oedema, whereas the control group developed compensated myocardial hypertrophy with no heart failure. PMCA1cko mice were also found to have a significantly higher degree of myocardial fibrosis on histology examination. Expression of other calcium handling genes such as PMCA4, NCX, SERCA2 and RyR remained unchanged. On the other hand, PMCA1HT mice demonstrated development of concentric myocardial hypertrophy after five weeks TAC whilst the wildtype controls developed eccentric myocardial hypertrophy. These data show that PMCA1 plays a major role in enabling heart to adapt with pressure overload and pathological hypertrophy. That is why following its deletion, the myocardium is unable to effectively respond to the pressure overload and as a result, decompensated heart failure develops. However, the loss of single allele of PMCA1 (PMCA1HT) does not appear to affect TAC induced cardiac hypertrophy. PMCA1's protective role during the development of pathological cardiac hypertrophy may help to explore novel treatment options for patients with heart failure. A mechanistic explanation for the development of dilated cardiomyopathy after PMCA1 deletion in cardiomyocytes would require further probing of the cellular pathways involved in hypertrophy and fibrosis. Future work to explore PMCA1's role should involve generation of a cardiac fibroblast specific PMCA1 knock out model to evaluate some of these pathways. Using a selective PMCA1 inhibitor such as caloxin 1b3, future TAC experiments would help to determine PMCA1's potential to be an effective therapeutic target for the treatment of heart failure.
- Heart Failure
- Plasma Membrane Ca ATPase 1 (PMCA1)
- Transverse Aortic Constriction (TAC)
The role of PMCA1 in the development of heart failure.
Nazir, T. (Author). 25 Nov 2022
Student thesis: Phd