Xie L.-H.,Medicine University of Medicine |
Shanmugam M.,Medicine University of Medicine |
Park J.Y.,Medicine University of Medicine |
Zhao Z.,Medicine University of Medicine |
And 4 more authors.
American Journal of Physiology - Cell Physiology | Year: 2012
Sarcolipin (SLN) is a key regulator of sarco(endo)plasmic reticulum (SR) Ca 2+-ATPase (SERCA), and its expression is altered in diseased atrial myocardium. To determine the precise role of SLN in atrial Ca 2+ homeostasis, we developed a SLN knockout (sln-/-) mouse model and demonstrated that ablation of SLN enhances atrial SERCA pump activity. The present study is designed to determine the long-term effects of enhanced SERCA activity on atrial remodeling in the sln-/- mice. Calcium transient measurements show an increase in atrial SR Ca 2+ load and twitch Ca 2+ transients. Patch-clamping experiments demonstrate activation of the forward mode of sodium/ calcium exchanger, increased L-type Ca 2+ channel activity, and prolongation of action potential duration at 90% repolarization in the atrial myocytes of sln-/- mice. Spontaneous Ca 2+ waves, delayed afterdepolarization, and triggered activities are frequent in the atrial myocytes of sln-/- mice. Furthermore, loss of SLN in atria is associated with increased interstitial fibrosis and altered expression of genes encoding collagen and other extracellular matrix proteins. Our results also show that the sln-/- mice are susceptible to atrial arrhythmias upon aging. Together, these findings indicate that ablation of SLN results in increased SERCA activity and SR Ca 2+ load, which, in turn, could cause abnormal intracellular Ca 2+ handling and atrial remodeling. © 2012 the American Physiological Society.