89 Heterozygous global deletion of Plasma Membrane Calcium Atpase 1 (PMCA1HT) may reduce cardiac remodelling after transverse aortic constriction in a murine model

Background Cardiovascular diseases remain a major cause of mortality worldwide. PMCA1 is the most prevalent isoform of PMCA in the heart. Our group has previously generated novel PMCA1 mutant mouse lines using Cre/loxP technology. Cardiomyocyte-specific PMCA1 knockout mice (PMCA1cko) develop severe cardiomyopathy with HF and heterozygote global PMCA1 knockout mice (PMCA1Ht) have elevated blood pressure. However, whether global heterozygous deletion of PMCA1Ht has any impact on cardiac remodelling after pathological stress resulting from pressure overload caused by transverse aortic constriction (TAC) remains uncertain. Methods For this study, 8 weeks old PMCA1Ht and wild type (WT) mice were grouped into TAC and sham operation cohorts. In mice subjected toTAC the thoracic aorta was ligated (over a curved blunt 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 5 week later and animals were sacrificed. Cardiac tissue samples were collected for histology, protein and RNA analysis. Results At the basal level, PMCA1Ht and wild type mice had no significant difference in the cardiac structure and function on echocardiogram and haemodynamic analysis. Basal expression of PMCA1 was approximately 50% lower in the PMCA1Ht mice whereas expression of other calcium handling genes including PMCA4, NCX, SERCA2 and RyR were similar in both groups. Five weeks after TAC, WT mice had worse LV function with a reduction in ejection fraction and fractional shortening, compared to PMCA1Ht mice from the same group. LV structure and function were preserved in the sham operation groups of both genotype. WT:TAC mice had a relatively higher expression of BNP, Collagen 1 and 3 compared to PMCA1Ht mice; however, expression of Bax (inducer of apoptosis) and Bcl2 (inhibitors of apoptosis) was similar in both genotypes. These findings suggest a higher degree of cardiac remodelling in the wild type mice as evidenced by worse LV function, higher expression of cardiac markers of hypertrophy and fibrosis. Interestingly in both the WT and PMCA1Ht groups post-TAC, there was a trend towards an increase in the mRNA expression of PMCA1 compared to the sham groups. Conclusion Our data indicates that global heterozygous deletion of PMCA1 may have a protective role for the heart after TAC. It appears to reduce cardiac remodelling in a pressure overload setting. Authors recommend further work with larger sample size to understand molecular mechanisms underpinning these findings. Conflict of Interest None