Heart failure is the common and final end point of cardiovascular disease. Seventy four percent of congestive heart failure patients also suffer from hypertension. Genome wide association studies (GWAS) have recently identified mutations in the ATP2B1 gene as having a strong association with hypertension risk. The ATP2B1 gene encodes the calcium extrusion pump, plasma membrane calcium ATPase (PMCA1), which also functions as a signalling molecule.Introduction
This project aims to examine the link between PMCA1 and blood pressure regulation, and cardiac structure and to determine if PMCA1 plays an important role in the development of high blood pressure.Methods
We generated a global PMCA1 heterozygous knockout mouse (PMCA1Ht), to study the role of PMCA1. Western blot analysis was used to determine PMCA1 protein level in aorta, heart, brain and kidney. To induce hypertension, three months old PMCA1Ht and wild type (WT) mice were infused via minipump with angiotensin II (1mg/Kg/daily) for two weeks. Control mice were infused with water. Systolic and diastolic blood pressures were measured using the tail-cuff method, before and after the pump implantation. Since sustained hypertension can lead to cardiac remodelling, the cardiac hypertrophic response after angiotensin II treatment was examined using echocardiography and by calculating heart weight to tibia length ratio. In addition, hearts were fixed, sectioned and stained with haematoxylin and eosin and cardiac myocyte size was quantified.Results
We characterise the global PMCA1Ht model, for the first time. PMCA1Ht mice had 46% to 52% reduction in PMCA1 protein expression compared to the WT, in aorta, heart, kidney and brain. At 3 months old we found that PMCA1Ht and WT had similar systolic and diastolic blood pressures. As expected, upon angiotensin II treatment, WT mice showed a significant increase in systolic BP (33.37 ± 2.91 mmHg) and diastolic BP (23.94 ± 4.56 mmHg). Interestingly, PMCA1Ht mice showed a significantly greater increase in systolic (62.24 ± 3.05 mmHg) and diastolic pressure (52.68 ± 4.67 mmHg), in comparison to the WT, P < 0.001. After angiotensin II treatment, echocardiography showed that PMCA1Ht mice had a significantly higher left ventricular mass to body weight ratio (4.78 ± 0.24), compared to WT mice (4.14 ± 0.17), P < 0.01. Moreover, PMCA1Ht mice showed a significantly higher heart weight to tibia length ratio and cardiomyocyte cell size (410 ± 18.7 µm2), compared to WT mice (340.4 ± 9.8 µm2), P < 0.01.Conclusion
Under angiotension II treatment PMCA1 deletion exacerbates the increase in blood pressure and cardiac hypertrophy. This provides evidence that PMCA1 is involved in blood pressure regulation and the development of hypertension, which supports the findings of the GWAS.