Abstract 3431: The Sarcolemmal Calcium Pump 4 (PMCA4) is a Powerful Regulator of Pathological Hypertrophy via the Nitric Oxide - Foxo3a Pathway
The plasma membrane calcium/calmodulin dependent ATPase (PMCA) ejects calcium from the myocardium but its role in diastolic relaxation is minor. We have therefore been exploring whether PMCA has a role in signaling. We have shown that the isoform 4b of PMCA (PMCA4b) regulates NO signaling from a specific subfraction of cardiac nNOS bound to it via a PDZ domain. Here we investigated whether PMCA4 is differently regulated in human heart failure and whether it is involved in regulating hypertrophic signals. In human failing hearts PMCA4 protein expression was reduced by 60% compared to normal hearts (n=3, P<0.01). PMCA4 was also downregulated by 25% in mouse hearts after transverse aortic constriction (TAC)(n=5, P<0.05). To investigate signal transmission by PMCA4 in the hypertrophic process, we subjected our PMCA4 knock-out (PMCA4−/−) mice to TAC for 5 weeks. PMCA4−/− mice displayed a significantly reduced hypertrophic response compared to wild type (WT) littermates. (Heart weight /tibia length ratio (HW/TL), PMCA4−/−: 6.74 ± 0.33 mg/mm, WT: 8.34 ± 0.88 mg/mm, P<0.05, n>10). Sham operated mice had HW/TL: 6.33 ± 0.29 mg/mm (KO) and 5.89 ± 0.22 mg/mm (WT). Echocardiography and LV pressure volume loops revealed that PMCA4 ablation protected the heart from abnormal left ventricular remodeling and contractile dysfunction in WT TAC. Cardiomyocyte cross sectional area and the hypertrophic markers ANP and BNP were also elevated in WT TAC, but not in PMCA4−/− . In contrast to the TAC model, the hypertrophic response was identical between PMCA4−/− and WT after chronic swimming exercise (4 weeks swimming, 2x90 minutes/day). Analysis of signaling pathways in response to TAC showed that phosphorylation of Akt was blunted in PMCA4−/−. Furthermore, the transcription factor FoxO3a, which is downstream of Akt, was also less activated in PMCA4−/−mice. Our findings suggest a crucial and novel role of PMCA4 as a specific regulator of pathological, but not physiological, hypertrophy and further strengthens the notion that PMCA4 is part of a key signaling pathway in the heart. In addition, ATPases, such as PMCA4, are choice drug targets and therefore our results potentially open the way for novel therapeutic approaches in cardiac hypertrophy and failure.