Sodium accumulation promotes diastolic dysfunction in end-stage heart failure following Serca2 knockout

Authors


Corresponding author W. E. Louch: Institute for Experimental Medical Research, 4.etg. Kirurgisk Bygning, Oslo University Hospital Ullevaal, 0407 Oslo, Norway.  Email: w.e.louch@medisin.uio.no

Abstract

Alterations in trans-sarcolemmal and sarcoplasmic reticulum (SR) Ca2+ fluxes may contribute to impaired cardiomyocyte contraction and relaxation in heart failure. We investigated the mechanisms underlying heart failure progression in mice with conditional, cardiomyocyte-specific excision of the SR Ca2+-ATPase (SERCA) gene. At 4 weeks following gene deletion (4-week KO) cardiac function remained near normal values. However, end-stage heart failure developed by 7 weeks (7-week KO) as systolic and diastolic performance declined. Contractions in isolated myocytes were reduced between 4- and 7-week KO, and relaxation was slowed. Ca2+ transients were similarly altered. Reduction in Ca2+ transient magnitude resulted from complete loss of SR Ca2+ release between 4- and 7-week KO, due to loss of a small remaining pool of SERCA2. Declining SR Ca2+ release was partly offset by increased L-type Ca2+ current, which was facilitated by AP prolongation in 7-week KO. Ca2+ entry via reverse-mode Na+–Ca2+ exchange (NCX) was also enhanced. Up-regulation of NCX and plasma membrane Ca2+-ATPase increased Ca2+ extrusion rates in 4-week KO. Diastolic dysfunction in 7-week KO resulted from further SERCA2 loss, but also impaired NCX-mediated Ca2+ extrusion following Na+ accumulation. Reduced Na+-K+-ATPase activity contributed to the Na+ gain. Normalizing [Na+] by dialysis increased the Ca2+ decline rate in 7-week KO beyond 4-week values. Thus, while SERCA2 loss promotes both systolic and diastolic dysfunction, Na+ accumulation additionally impairs relaxation in this model. Our observations indicate that if cytosolic Na+ gain is prevented, up-regulated Ca2+ extrusion mechanisms can maintain near-normal diastolic function in the absence of SERCA2.

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