Abstract 9368: Plasma Membrane Calcium ATPase Isoform 1 Protects the Heart from Cardiomyopathy, Arrhythmias and Hypertension

Abstract

With 1 in 3 people in the USA dying as a result of cardiovascular disease, and the incidence of these diseases rapidly increasing in the developing world, it is essential that we continue to provide mechanistic insights into their development and progression. Several recent human genome wide association studies have identified single nucleotide polymorphisms in the plasma membrane calcium ATPase isoform 1 (PMCA1) gene as the strongest association with hypertension and blood pressure variance; hypertension along with cardiomyopathy and arrhythmias are central features of heart failure. In this study we provide evidence that PMCA1, which is a transmembrane calcium transporter known to eject calcium from the cell, is involved in all of these key features of heart failure. To elucidate the role of PMCA1 in cardiac function we generated mice carrying a cardiomyocyte-specific gene deletion of PMCA1 (PMCA1 cko ). In response to pressure overload hypertrophic stress induced by transverse aortic constriction (TAC) PMCA1 cko mice displayed accelerated cardiac dysfunction shown by significantly reduced fractional shortening compared to controls (FS; PMCA1 cko /TAC: 21±2%, PMCA1 f/f /TAC 32±3%, PMCA1 cko /Sham and [alpha]-MHC-Cre/TAC 35±2%, p <0.05, n=6). This was accompanied by increased lung weight/body weight in PMCA1 cko /TAC (11.5±1 vs 7.8±0.8 mg/g in PMCA1 f/f /TAC, p <0.05, n=6), greater cardiomyocyte cross-sectional area and significantly elevated interstitial fibrosis. Our data shows that in the myocardium PMCA1 has an additional role in stabilising cardiac rhythm. At 3 months of age PMCA1 cko displayed episodes of spontaneous ventricular tachycardia whilst exhibiting an 80% downregulation in the expression of the voltage gated sodium channel Na v 1.5 and a significant reduction in the corresponding current. To investigate the relationship between PMCA1 and blood pressure we generated PMCA1 heterozygous knockout mice (PMCA1 Ht ) in which both systolic and diastolic carotid pressure was significantly increased in PMCA1 Ht in comparison to wild type littermates. In conclusion, this data addresses the mechanistic basis for the association of PMCA1 with hypertension, cardiomyopathy and arrhythmias which are key contributors to heart failure.